1,2,4-thiazoloidin-3-one derivatives and their use in the treatment of cancer

ABSTRACT

According to the invention there is provided a compound of formula (I) wherein: A represents C(═N—W-D) or S; B represents S or C(—NH—W-D); when: A represents C(═N—W-D) and B represents S then the bond between B and the NH atom is a single bond; or A represents S and B represents C(—NH—W-D) then the bond between B and the NH atom is a double bond; X represents -Q-[CR x R y ] n —; W represents —[CR x R y ] m — or —C(O)—[CR x R y ] p —; Q represents a bond, —N(R a )—, —S—, or —O—; A 1  to A 5  respectively represent C(R 1 ), C(R 2 ), C(R 3 ), C(R 4 ) and C(R 5 ), or, alternatively, up to two of A 1  to A 5  may independently represent N; D represents phenyl, pyridyl or pyrimidinyl optionally substituted by one or more R 6  groups, which compounds are useful in the treatment of cancer.

FIELD OF THE INVENTION

This invention relates to pharmaceutically-useful compounds. Theinvention also relates to the use of such compounds in the treatment ofcancer.

BACKGROUND

AMP-activated protein kinase (AMPK) represents a new target for thetreatment of several diseases, including cancer.

Excess adiposity is associated to different degrees with an increasedrisk of developing cancers, such as colorectal adenomas, breast cancer(postmenopausal), endometrial cancer, kidney cancer, oesophagealadenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer,gallbladder cancer, liver cancer and cervical cancer (Calle and Kaaks(2004), Nature Reviews Cancer, 4, 579-591).

Investigations have demonstrated that cancer cells require high rates offatty acid and protein synthesis for their invasive growth and survival.Studies have shown that inhibition of cancer cell proliferation ispossible using AMPK activators. The effects are associated withdown-regulation of mTOR and eEF2. AMPK activators also suppress lipidsynthesis in tumour cells. It has also been shown that it is a linkbetween AMPK and other anti-cancer targets such as LKB1 and caspase-3activation.

Cancer cells use glucose at a higher rate compared to normal cells(Warburg O, 1956). Instead of mitochondrial oxidative phosphorylation toproduce ATP, cancer cells metabolise glucose via hydrolysis.

Recent studies suggest that hyperinsulinemia is correlated among otherthings to the incidence of colon and lethal breast and prostate cancer.

Elevated plasma free fatty acids (FFAs) stimulate pancreatic β-cells andis one cause of hyperinsulinemia.

In prostate cancer, hyperinsulinemia has been shown to be prospectiverisk factor for death and data support that the insulin level could beused as a marker of prostate cancer prognosis (Hammarsten and Högstedt(2005) European Journal of Cancer, 41, 2887).

Several mechanisms may link hyperinsulinemia to the incidence andoutcome of breast cancer. Firstly, chronic hyperinsulinemia results inincreased production of ovarian testosterone and oestrogen andinhibition of hepatic production of sex hormone binding globulin, asex-hormonal profile that is associated with breast cancer. Secondly,hyperinsulinemia suppresses hepatic production of insulin-like growthfactor binding protein-1 (IGFBP-1), and thus increases circulatinglevels of IGF-1, which has potent mitogenic effect on breast tissue.Thirdly, insulin itself may have a direct mitogenic effect on breastcancer cells.

The study by Hardy et al ((2005), J. Biol. Chem. 280, 13285) shows thatFFAs directly stimulate the growth of breast cancer cells in a GPR40dependent manner. Moreover, expression studies performed on tumor tissueisolated from 120 breast cancer patient shows a frequent expression ofGPR40 emphasizing the clinical relevance of the findings of Hardy (see,for example, Ma et al, Cancer Cell (2004) 6, 445).

Another expression study on clinical material from colon cancer patientssuggests that similar mechanisms could be relevant also in thesemalignancies (seehttp://www.ncbi.nlm.nih.gov/projects/geo/gds/gds_browse.cgi?gds=1263).

Cancer cells in general exhibit an aberrant metabolism compared tonon-transformed cells. Neoplastic cells synthesise lipids to a muchlarger extent than their normal counterparts and metabolise glucosedifferently. It has been suggested that this aberrant metabolismconstitutes a therapeutic target. By interfering with one or,preferably, several of the pathways controlling cellular metabolism,cancer cells would be more sensitive than non-transformed cells, thuscreating a therapeutic window. Examples of pathways/targets includeglycolysis interfering agents, lipid synthesis pathway, AMPK activatingagents and agents affecting mitochondrial function.

AMP-activated protein kinase (AMPK) is a protein kinase enzyme thatconsists of three protein sub-units and is activated by hormones,cytokines, exercise, and stresses that diminish cellular energy state(e.g. glucose deprivation). Activation of AMPK increases processes thatgenerate adenosine 5′-triphosphate (ATP) (e.g., fatty-acid oxidation)and restrains others such as fatty acid-, glycerolipid- andprotein-synthesis that consume ATP, but are not acutely necessary forsurvival. Conversely, when cells are presented with a sustained excessof glucose, AMPK activity diminishes and fatty acid-, glycerolipid- andprotein-synthesis are enhanced. AMPK thus is a protein kinase enzymethat plays an important role in cellular energy homeostasis. Therefore,the activation of AMPK is coupled to glucose lowering effects andtriggers several other biological effects, including the inhibition ofcholesterol synthesis, lipogenesis, triglyceride synthesis, and thereduction of hyperinsulinemia.

Given the above, AMPK is a preferred target for the treatment of themetabolic syndrome and especially type 2 diabetes. AMPK is also involvedin a number of pathways that are important for many different diseases(e.g. AMPK is also involved in a number of pathways that are importantin CNS disorders, fibrosis, osteoporosis, heart failure and sexualdysfunction).

AMPK is also involved in a number of pathways that are important incancer. Several tumour suppressors are part of the AMP pathway. AMPKacts as a negative regulator of the mammalian TOR (mTOR) and EF2pathway, which are key regulators of cell growth and proliferation. Thederegulation may therefore be linked to diseases such as cancer (as wellas diabetes). AMPK activators may therefore be of utility as anti-cancerdrugs.

Current anti-diabetic drugs (e.g. metformin, glitazones) are known tonot be significantly potent AMPK activators, but only activate AMPKindirectly and with low efficacy. However, due to the biological effectsof AMPK activation at the cell level, compounds that are AMPKactivators, and preferably direct activators of AMPK, may find utilityas anti-cancer drugs, as well as for the treatment of many otherdiseases.

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Throughout this disclosure, various publications, patents and publishedpatent specifications are referenced by an identifying citation. Thedisclosures of these publications, patents and published patentspecifications are hereby incorporated by reference into the presentdisclosure to more fully describe the state of the art to which thisinvention pertains.

Keilen et al., Acta Chem. Scand. 1988, B42, 362-366 describe theformation of 1,2,4-thiadiazolo activated pyrimidinones. There is alsodisclosed a specific 1,2,4-thiadiazolo-3-ones. However, the documentdoes not disclose any biological effects associated with the disclosedcompounds, nor does it disclose 1,2,4-thiadiazolo-3-ones substituted atthe 5-position with an amide or amine derivative bearing at least onesubstituted aromatic ring.

Kaugars et al., J. Org. Chem. 1979, 44(22), 3840-3843 describe 5-phenyl-and 5-methyl-substituted phenyl urea derivatives of 1,2,4,thiadiazol-3-one that are substituted in the 2-position with a methylgroup. There is no mention of any biological effects associated with thedisclosed compounds.

Cho et al J. Heterocyclic Chem. 1991, 28, 1645-1649 discloses various1,2,4-thiadiazol-3-ones. However, there is no disclosure of such1,2,4-thiadiazol-3-ones, in which the 2-position and 5-position containsubstituents bearing an aromatic ring.

U.S. Pat. No. 4,093,624 describes 1,2,4 thiadiazolidin-3-one compounds,described as having antimicrobial activity, which are substituted by a—NH₂ or —NHAc in the 5-position and H or ribofuranosyls in the2-position. There is no disclosure of 1,2,4-thiadiazol-3-ones in whichthe 2-position and 5-position contain substituents bearing an aromaticring.

Castro et al., Bioorg. Med. Chem. 2008, 16, 495-510 describesthiadiazolidinone derivates as GSK-3β inhibitors that are potentiallyuseful for the treatment of Alzheimer's disease. There is no mentionthat such compounds may be useful as AMPK activators. Further, there isno mention of 1,2,4-thiadiazol-3-ones substituted at the 5-position withan amide or amine derivative bearing at least one substituted aromaticring.

Martinez et al. Bioorg. Med. Chem. 1997, 7, 1275-1283 describesarylimino-1,2,4-thiadiazolidinone derivatives as potassium channelopeners that are potentially useful for the treatment of diseasesinvolving smooth muscle contraction (e.g. hypertension). However, thereis no disclosure of such thiadiazolidinones substituted at the2-position with an aromatic group.

US patent application publication number 2003/0195238 describesthiadiazolidine derivates as GSK-3β inhibitors that are potentiallyuseful for the treatment of Alzheimer's disease. However, this documentmainly relates to thiadiazolidines substituted by twocarbonyl/thiocarbonyl groups (thereby forming e.g. a3,5-dioxo-thiadiazolidine or a 3-thioxo-5-oxo-thiadiazolidine). Further,it mainly relates to compounds in which both nitrogen atoms of thethiadiazolidine are substituted. The document does not relate tothiadiazolidines substituted at the 2-position with a group bearing anaromatic group and at the 5-position with an amino or amido derivativebearing an aromatic group.

International patent applications WO 2007/010273 and WO 2007/010281 bothdisclose e.g. thiazolidin-4-one and1,1-dioxo-1,5-dihydro-[1,4,2]dithiazole compounds that are able toantagonize the stimulatory effect of FFAs on cell proliferation whentested in an assay using a human breast cancer cell line (MDA-MB-231).Such compounds are thus indicated in the treatment of cancer and/or asmodulators of FFAs. However, these documents do not disclose or suggestthiadiazolidinones.

DISCLOSURE OF THE INVENTION

According to embodiments of the invention, there is provided a compoundof formula I,

wherein:A represents C(═N—W-D) or S;B represents S or C(—NH—W-D);when:A represents C(═N—W-D) and B represents S then the bond between B andthe NH atom is a single bond; orA represents S and B represents C(—NH—W-D) then the bond between B andthe NH atom is a double bond;X represents -Q-[CR^(x)R^(y)]_(n)—;W represents —[CR^(x)R^(y)]_(m)— or —C(O)-[CR^(x)R^(y)]_(p)—;Q represents a bond, —N(R^(a))—, —S—, or —O—;A₁ to A₅ respectively represent C(R¹), C(R²), C(R³), C(R⁴) and C(R⁵),or, alternatively, up to two of A₁ to A₅ may independently represent N;D represents phenyl, pyridyl or pyrimidinyl optionally substituted byone or more R⁶ groups;R^(x) and R^(y), on each occasion when used herein, are independentlyselected from H, halo, C₁₋₆ alkyl (optionally substituted by one or morehalo atoms), aryl (optionally substituted by one or more halo atoms) orR^(x) and R^(y) are linked to form, along with the carbon atom to whichthey are attached, a non-aromatic 3- to 8-membered ring, optionallycontaining 1 to 3 heteroatoms selected from O, S and N, which ring isitself optionally substituted by one or more substituents selected fromhalo or C₁₋₆ alkyl (optionally substituted by one or more halo atoms);R¹ to R⁵ independently represent H, halo, —R⁷, —CF₃, —CN, —NO₂, —C(O)R⁷,—C(O)OR⁷, —C(O)—N(R^(7a))R^(7b), —N(R^(7a))R^(7b), —N(R⁷)₃ ⁺, —SR⁷,—OR⁷, —NH(O)R⁷, —SO₃R⁷, aryl or heteroaryl (which aryl and heteroarylgroups are themselves optionally and independently substituted by one ormore groups selected from halo and R¹⁶), or any two of R¹ to R⁵ whichare adjacent to each other are optionally linked to form, along with twoatoms of the essential benzene ring in the compound of formula I, anaromatic or non-aromatic 3- to 8-membered ring, optionally containing 1to 3 heteroatoms selected from O, S and N, which ring is itselfoptionally substituted by one or more substituents selected from halo,—R⁷, —OR⁷ and ═O;R⁶ independently represents, on each occasion when used herein, cyano,—NO₂, halo, —R⁸, —OR⁸, —N(R⁸)C(O)R⁸, —NR⁹R¹⁰, —SR¹¹, —Si(R¹²)₃,—OC(O)R¹³, —C(O)OR¹³, —C(O)R¹⁴, —C(O)NR^(15a)R^(15b),—S(O)₂NR^(15c)R^(15d) aryl or heteroaryl (which aryl and heteroarylgroups are themselves optionally and independently substituted by one ormore groups selected from halo and R¹⁶), or any two R⁶ groups which areadjacent to each other are optionally linked to form, along with twoatoms of the essential benzene ring in the compound of formula I, anaromatic or non-aromatic 3- to 8-membered ring, optionally containing 1to 3 heteroatoms selected from O, S and N, which ring is itselfoptionally substituted by one or more substituents selected from halo,—R⁷, —OR⁷ and ═O;R⁷, on each occasion when used herein, is selected from H or C₁-C₆alkyl, C₁-C₆ cycloalkyl, aryl and heteroaryl (wherein the latter fourgroups are optionally substituted by one or more halo atoms);R^(7a) and R^(7b) are independently selected from H, or C₁-C₆ alkyl,C₁-C₆ cycloalkyl, aryl and heteroaryl, or R^(7a) and R^(7b) areoptionally linked to form, along with the nitrogen atom to which theyare attached, an aromatic or non-aromatic 3- to 8-membered ring,optionally containing 1 to 3 heteroatoms selected from O, S and N, whichring is itself optionally substituted by one or more substituentsselected from halo, —R⁷, —OR⁷ and ═O;R^(a), R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(15a), R^(15b), R^(15c) andR^(15d), on each occasion where used herein, independently represent Hor R¹⁶;R¹⁶ represents, on each occasion when used herein, C₁₋₆ alkyl optionallysubstituted by one or more halo atoms;n represents 0 or, more preferably, 1 or 2;m represents 2 or, more preferably, 1 or 0;p represents 2 or, more preferably, 1 or 0;or a pharmaceutically-acceptable salt or solvate, or a pharmaceuticallyfunctional derivative thereof,provided that when D is phenyl, then at least one of A₁ to A₅ is not(C—H) and/or D is substituted by one or more —R⁶ groups.

Pharmaceutically-acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound of formula I with one or more equivalents of anappropriate acid or base, optionally in a solvent, or in a medium inwhich the salt is insoluble, followed by removal of said solvent, orsaid medium, using standard techniques (e.g. in vacuo, by freeze-dryingor by filtration). Salts may also be prepared by exchanging acounter-ion of a compound of formula I in the form of a salt withanother counter-ion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable addition salts include thosederived from mineral acids, such as hydrochloric, hydrobromic,phosphoric, metaphosphoric, nitric and sulphuric acids; from organicacids, such as tartaric, acetic, citric, malic, lactic, fumaric,benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and frommetals such as sodium, magnesium, or preferably, potassium and calcium.

“Pharmaceutically functional derivatives” of compounds of formula I asdefined herein includes ester derivatives and/or derivatives that have,or provide for, the same biological function and/or activity as anyrelevant compound. Thus, for the purposes of this invention, the termalso includes prodrugs of compounds of formula I.

The term “prodrug” of a relevant compound of formula I includes anycompound that, following oral or parenteral administration, ismetabolised in vivo to form that compound in anexperimentally-detectable amount, and within a predetermined time (e.g.within a dosing interval of between 6 and 24 hours (i.e. once to fourtimes daily)). For the avoidance of doubt, the term “parenteral”administration includes all forms of administration other than oraladministration.

Prodrugs of compounds of formula I may be prepared by modifyingfunctional groups present on the compound in such a way that themodifications are cleaved, in vivo when such prodrug is administered toa mammalian subject. The modifications typically are achieved bysynthesizing the parent compound with a prodrug substituent. Prodrugsinclude compounds of formula I wherein a hydroxyl, amino, sulfhydryl,carboxy or carbonyl group in a compound of formula I is bonded to anygroup that may be cleaved in vivo to regenerate the free hydroxyl,amino, sulfhydryl, carboxy or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxy functional groups, esters groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elsevier, N.Y. -Oxford (1985).

Compounds of formula I, as well as pharmaceutically-acceptable salts,solvates and pharmaceutically functional derivatives of such compoundsare, for the sake of brevity, hereinafter referred to together as the“compounds of formula I”.

Compounds of formula I may contain double bonds and may thus exist as E(entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. All such isomers and mixtures thereof are included withinthe scope of the invention.

Compounds of formula I may exist as regioisomers and may also exhibittautomerism. All tautomeric forms and mixtures thereof are includedwithin the scope of the invention. For example, the following tautomersare included within the scope of the invention:

Compounds of formula I contain one or more asymmetric carbon atoms andmay therefore exhibit optical and/or diastereoisomerism.Diastereoisomers may be separated using conventional techniques, e.g.chromatography or fractional crystallisation. The various stereoisomersmay be isolated by separation of a racemic or other mixture of thecompounds using conventional, e.g. fractional crystallisation or HPLC,techniques. Alternatively the desired optical isomers may be made byreaction of the appropriate optically active starting materials underconditions which will not cause racemisation or epimerisation (i.e. a‘chiral pool’ method), by reaction of the appropriate starting materialwith a ‘chiral auxiliary’ which can subsequently be removed at asuitable stage, by derivatisation (i.e. a resolution, including adynamic resolution), for example with a homochiral acid followed byseparation of the diastereomeric derivatives by conventional means suchas chromatography, or by reaction with an appropriate chiral reagent orchiral catalyst all under conditions known to the skilled person. Allstereoisomers and mixtures thereof are included within the scope of theinvention.

Unless otherwise stated, the term “alkyl” refers to an unbranched orbranched, cyclic, saturated or unsaturated (so forming, for example, analkenyl or alkynyl)hydrocarbyl radical, which may be substituted orunsubstituted (with, for example, one or more halo atoms). Where theterm “alkyl” refers to an acyclic group, it is preferably C₁₋₁₀ alkyland, more preferably, C₁₋₆ alkyl (such as ethyl, propyl, (e.g. n-propylor isopropyl), butyl (e.g. branched or unbranched butyl), pentyl or,more preferably, methyl). Where the term “alkyl” is a cyclic group(which may be where the group “cycloalkyl” is specified), it ispreferably C₃₋₁₂ cycloalkyl and, more preferably, C₅₋₁₀ (e.g. C₅₋₇)cycloalkyl.

When used herein, alkylene refers to C₁₋₁₀ (e.g. C₁₋₆) alkylene and,preferably C₁₋₃ alkylene, such as pentylene, butylene (branched orunbranched), preferably, propylene (n-propylene or isopropylene),ethylene or, more preferably, methylene (i.e. —CH₂—).

The term “halogen”, when used herein, includes fluorine, chlorine,bromine and iodine.

The term “aryl” when used herein includes C₆₋₁₄ (such as C₆₋₁₃ (e.g.C₆₋₁₀)) aryl groups. Such groups may be monocyclic, bicyclic ortricyclic and have between 6 and 14 ring carbon atoms, in which at leastone ring is aromatic. The point of attachment of aryl groups may be viaany atom of the ring system. However, when aryl groups are bicyclic ortricyclic, they are linked to the rest of the molecule via an aromaticring. C₆₋₁₄ aryl groups include phenyl, naphthyl and the like, such as1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Mostpreferred aryl groups include phenyl.

The term “heteroaryl” when used herein refers to an aromatic groupcontaining one or more heteroatom(s) (e.g. one to four heteroatoms)preferably selected from N, O and S (so forming, for example, a mono-,bi-, or tricyclic heteroaromatic group). Heteroaryl groups include thosewhich have between 5 and 14 (e.g. 10) members and may be monocyclic,bicyclic or tricyclic, provided that at least one of the rings isaromatic. However, when heteroaryl groups are bicyclic or tricyclic,they are linked to the rest of the molecule via an aromatic ring.Heterocyclic groups that may be mentioned include benzothiadiazolyl(including 2,1,3-benzothiadiazolyl), isothiochromanyl and, morepreferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl,benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl,benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including2,1,3-benzoxadiazolyl), benzoxazinyl (including3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl,benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl,carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl,imidazo[1,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl,isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl,isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably,1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl,phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl),tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl,thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl,1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents onheteroaryl groups may, where appropriate, be located on any atom in thering system including a heteroatom. The point of attachment ofheteroaryl groups may be via any atom in the ring system including(where appropriate) a heteroatom (such as a nitrogen atom), or an atomon any fused carbocyclic ring that may be present as part of the ringsystem. Heteroaryl groups may also be in the N- or S-oxidised form.Particularly preferred heteroaryl groups include pyridyl, pyrrolyl,quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl,oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl,thiophenetyl, thiophenyl, pyranyl, carbazolyl, acridinyl, quinolinyl,benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl.Particularly preferred heteroaryl groups include monocylic heteroarylgroups.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of formula I may be the same, the actualidentities of the respective substituents are not in any wayinterdependent. For example, given that D may be optionally substitutedby one or more R⁶ groups, then those R⁶ groups may be the same ordifferent. Similarly, in the situation in which R⁶ and R⁷ are both arylgroups substituted by one or more C₁₋₆ alkyl groups, the alkyl groups inquestion may be the same or different. Additionally, in the situation inwhich R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(15a), R^(15b), R^(15c) andR^(15d) independently represent R¹⁶ then those R¹⁶ groups may be thesame or different.

For the avoidance of doubt, when a term such as “A₁ to A₅” is employedherein, this will be understood by the skilled person to mean any of(i.e. some or all, as applicable) A₁, A₂, A₃, A₄ and A₅ inclusively.

All individual features (e.g. preferred features) mentioned herein maybe taken in isolation or in combination with any other feature(including preferred feature) mentioned herein (hence, preferredfeatures may be taken in conjunction with other preferred features, orindependently of them).

The skilled person will appreciate that in certain preferred embodimentsof the compounds of the invention, some or all of the provisos (a) to(c) above will become redundant (for example, where it is stated that atleast one (or both) of the A₁ to A₅-containing ring and/or ring Dcarries a substituent other than hydrogen, then all of the provisos (a)to (c) above are redundant).

In an embodiment of the invention, there is provided a compound offormula I wherein:

A represents C(═N—W-D) and W represents —C(O)—[CR^(x)R^(y)]_(p)—.

In a further embodiment of the invention, there is provided a compoundof formula I wherein:

A represents C(═N—W-D) and W represents —[CR^(x)R^(y)]_(m)—.

In yet a further embodiment of the invention, there is provided acompound of formula I wherein:

B represents C(—NH—W-D) and W represents —C(O)—[CR^(x)R^(y)]_(p)—.

In a yet further embodiment of the invention, there is provided acompound of formula I wherein:

B represents C(—NH—W-D) and W represents —[CR^(x)R^(y)]_(m)—.

Preferred compounds of formula I include those in which at least one ofA₁ to A₅ is not (C—H) and D is substituted by one or more —R⁶ groups. Itis preferred that either the A₁ to A₅-containing ring or ring D issubstituted with a substituent other than H.

When it is stated herein that at least one of A₁ to A₅ is not (C—H) orthat ring D is substituted with a substituent other than H, we mean thateither:

one of A₁ to A₅ represents N or, preferably, one of A₁ to A₅ representsC(R¹), C(R²), C(R³), C(R⁴) or C(R⁵) (as appropriate) in which at leastone of R¹, R², R³, R⁴ or R⁵ represents a substituent other than H (i.e.at least one of R¹ to R⁵ substituent is present that represents halo,—R⁷, —CF₃, —CN, —NO₂, —C(O)R⁷, —C(O)OR⁷, —C(O)—N(R^(7a))R^(7b),—N(R^(7a))R^(7b), —N(R⁷)₃ ⁺, —SR⁷, —OR⁷, —NH(O)R⁷, —SO₃R⁷, aryl orheteroaryl (which aryl and heteroaryl groups are themselves optionallyand independently substituted by one or more groups selected from haloand R¹⁶), or any two of R¹ to R⁵ which are adjacent to each other arelinked as defined herein); orring D represents pyridyl or pyrimidinyl or, preferably, ring D issubstituted by one or more R⁶ groups.

More preferred compounds of formula I that may be mentioned includethose in which: one of A₁ to A₅ represents N or, preferably, one of A₁to A₅ represents C(R¹), C(R²), C(R³), C(R⁴) or C(R⁵) (as appropriate) inwhich at least one of R¹, R², R³, R⁴ or R⁵ represents a substituentother than H (e.g. a substituent as defined herein); and

ring D represents pyridyl or pyrimidyl or, preferably, ring D is phenylsubstituted by one or more R⁶ groups.

Preferred compounds of formula I that may be mentioned include those inwhich:

A represents S.

More preferred compounds of formula I that may be mentioned includethose in which:

B represents S.

Compounds of formula I that may be mentioned include those in which:

each—[CR^(x)R^(y)]— unit may be independently selected from:

-   -   (a) a unit wherein R^(x) and R^(y) are independently selected        from H, halo, C₁₋₆ alkyl (optionally substituted by one or more        halo atoms); and    -   (b) a unit wherein R^(x) and R^(y) are linked to form, along        with the carbon atom to which they are attached, a non-aromatic        3- to 8-membered ring, optionally containing 1 to 3 heteroatoms        selected from O, S and N, which ring is itself optionally        substituted by one or more substituents selected from halo or        C₁₋₆ alkyl (optionally substituted by one or more halo atoms),    -   provided that no more than one unit is selected from (b);        (e.g. each —[CR^(x)R^(y)]— unit may be independently selected        from:    -   (a) a unit wherein R^(x) and R^(y) are independently selected        from H, halo, C₁₋₃ alkyl (optionally substituted by one or more        halo atoms) (e.g. at least one of R^(x) and R^(y) is H);    -   (b) a unit wherein R^(x) and R^(y) are linked to form, along        with the carbon atom to which they are attached, a non-aromatic        ring selected from cyclobutyl, cyclopentyl, cyclohexyl or, more        particularly, cyclopropyl, which ring is itself optionally        substituted by one or more substituents selected from halo or        C₁₋₆ alkyl (optionally substituted by one or more halo atoms),    -   provided that no more than one unit is selected from (b)).

Compounds of formula I that may be mentioned include those in which:

R^(x) and R^(y) are linked to form, along with the carbon atom to whichthey are attached, a non-aromatic 3- to 8-membered ring, optionallycontaining 1 to 3 heteroatoms selected from O, S and N, which ring isitself optionally substituted by one or more substituents selected fromhalo and/or C₁₋₆ alkyl (optionally substituted by one or more haloatoms).

Further compounds of formula I that may be mentioned include those inwhich:

R^(x) and R^(y) are linked to form, along with the carbon atom to whichthey are attached, a cyclobutyl, cyclopentyl, cyclohexyl or, morepreferably, cyclopropyl ring which ring is itself optionally substitutedby one or more substituents selected from halo and/or C₁₋₆ alkyl(optionally substituted by one or more halo atoms, or more preferablyunsubstituted).

Further compounds of formula I that may be mentioned include those inwhich: one —[CR^(x)R^(y)]— unit forms a non-aromatic 3- to 8-memberedring, optionally containing 1 to 3 heteroatoms selected from O, S and N,which ring is itself optionally substituted by one or more substituentsselected from halo or C₁₋₆ alkyl (optionally substituted by one or morehalo atoms) and, if other —[CR^(x)R^(y)]— units are present, then theadditional R^(x) and R^(y) groups are independently selected from H,halo, C₁₋₆ alkyl (optionally substituted by one or more halo atoms) oraryl (optionally substituted by one or more halo atoms).

Further compounds of formula I that may be mentioned include those inwhich: one —[CR^(x)R^(y)]— unit is linked to form a cyclobutyl,cyclopentyl, cyclohexyl or, more preferably, cyclopropyl ring which ringis itself optionally substituted by one or more substituents selectedfrom halo or C₁₋₆ alkyl (optionally substituted by one or more haloatoms, or more preferably unsubstituted) and, if other —[CR^(x)R^(y)]—units are present, then the additional R^(x) and R^(y) groups areindependently selected from phenyl (optionally substituted by one ormore halo atoms) or, more preferably, H, halo, C₁₋₆ alkyl (optionallysubstituted by one or more halo atoms).

The above preferences for —[CR^(x)R^(y)]— apply particularly in respectof those compounds in which the relevant unit is part of the substituentX.

Compounds of formula I that may be mentioned include those in which:

R^(x) and R^(y) are independently selected from phenyl (optionallysubstituted by one or more halo atoms) or, more preferably, H, halo,C₁₋₆ alkyl (optionally substituted by one or more halo atoms).

Further compounds of formula I that may be mentioned include those inwhich:

Q represents —S—, preferably, —N(CH₃)—, —O— or, more preferably, a bond.

Compounds of formula I that may be mentioned include those in which:

when X represents -Q-[CR^(x)R^(y)]_(n)—, then the —[CR^(x)R^(y)]_(n)—moiety preferably represents —CR^(x)R^(y)— (e.g. —CH₂—, —C(—CH₂CH₂—)—,i.e. —C(cyclopropyl)-, or —C(H)(aryl)-) or —[CR^(x)R^(y)]₂— (e.g.—CH₂CH₂—):when n represents 1, then R^(x) and R^(y) independently represent C₁₋₆(e.g. C₁₋₃) alkyl or, preferably, hydrogen or aryl (e.g. phenyl;optionally substituted by one or more halo, e.g. chloro, atoms, soforming e.g. a chlorophenyl group), or, R^(x) and R^(y) are linkedtogether to form a non-aromatic carbocyclic 3- to 6-membered spirocycle(preferably cyclopropyl), which ring is preferably unsubstituted;both R^(x) and R^(y), when attached to the same carbon atom, preferablydo not represent optionally substituted aryl;when n represents 2, then R^(x) and R^(y) independently represent C₁₋₆(e.g. C₁₋₃) alkyl or, preferably, hydrogen;e.g. when Q represents a bond, n represents 1 or 2.

Most preferred groups that X may represent include —CH₂—, —CH₂CH₂—,—O—CH₂CH₂—, —N(CH₃)—CH₂CH₂—, —S—CH₂CH₂—, 1,1-cyclopropyl and—C(H)(4-chlorophenyl)- (i.e. it is preferred that X is not a directbond, but represents a group containing at least one linking atom).

Compounds of formula I that may be mentioned include those in which:

m and p independently represent 0 or 1;when W represents —[CR^(x)R^(y)]_(m)— or —[CR^(x)R^(y)]_(p), then R^(x)and R^(y) independently represent C₁₋₆ alkyl or, preferably hydrogen;W represents a direct bond (i.e. m represents 0), —CH₂—, —C(O)— (i.e. prepresents 0) or —C(O)CH₂—.

The A₁ to A₅-containing ring may be pyridyl (e.g. 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl or 6-pyridyl), but is preferably phenyl. The D ringis preferably pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridylor 6-pyridyl) or, more preferably, phenyl. Each ring may beunsubstituted or substituted with one or two substituents defined herein(by R¹ to R⁶, as appropriate). As stated herein, in a preferredembodiment of the invention, one of these rings is substituted with atleast one substituent other than H as defined herein (by R¹ to R⁶, asappropriate).

Most preferred compounds of formula I include those in which:

A₁ to A₅ respectively represent C(R¹), C(R²), C(R³), C(R⁴) and C(R⁵);D represents phenyl, pyridyl or pyrimidinyl optionally substituted byone or more R⁶ groups;R^(x) and R^(y), on each occasion when used herein, are independentlyselected from fluoro, preferably, H, C₁₋₆ alkyl (optionally substitutedby one or more fluoro atoms), aryl (optionally substituted by one ormore halo, e.g. chloro atoms) or R^(x) and R^(Y) are linked to form,along with the carbon atom to which they are attached, a non-aromatic 3-to 8-membered ring (e.g. 3- to 6-membered ring), which ring is itselfoptionally substituted by one or more substituents selected from fluoroand/or C₁₋₆ (e.g. C₁₋₃, such as C₁₋₂) alkyl (optionally substituted byone or more fluoro atoms), but which 3- to 8(e.g. 3- to 6-) memberedring is preferably unsubstituted (e.g. unsubstituted cyclopropyl);R¹ to R⁵ independently represent —CN, —N(R^(7a))R^(7b), —N(R⁷)₃ ⁺, —SR⁷or, preferably, H, halo (e.g. chloro or fluoro), —R⁷, —CF₃,—C(O)—N(R^(7a))R^(7b), —OR⁷ or heteroaryl (e.g. a 5- or 6-memberedheteroaryl group preferably containing one to three heteroatoms(preferably nitrogen heteroatoms), and which heteroaryl group isoptionally substituted by one or more groups selected from R¹⁶ and,preferably halo, e.g. chloro);R⁶ independently represents, on each occasion when used herein, —NO₂,—NR⁹R¹⁰, —SR¹¹, or, preferably, cyano, halo, —R⁸ or —OR⁸;R⁷, on each occasion when used herein, is selected from H and C₁₋₆ (e.g.C₁₋₃) alkyl (e.g. methyl) optionally substituted by one or more fluoroatoms (so forming for example a —CHF₂ or, preferably a —CF₃ group);R^(7a) and R^(7b) are independently selected from H and C₁₋₆ (e.g. C₁₋₃)alkyl (e.g. methyl) optionally substituted by one or more fluoro atoms(so forming for example a —CHF₂ or, preferably a —CF₃ group); or R^(7a)and R^(7b) are optionally linked to form, along with the nitrogen atomto which they are attached, an aromatic or non-aromatic 3- to 6-memberedring (preferably an aromatic 5- or 6-membered ring), optionallycontaining 1 to 3 heteroatoms selected from O, S and N (preferably Nheteroatoms), which ring is itself optionally substituted by one or moresubstituents selected from fluoro, —R⁷ and ═O; R^(a), R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R^(15a), R^(15b), R^(15c) and R^(15d), on each occasionwhere used herein, independently represent H or R¹⁶ (but R^(a) and R⁸more preferably represent R¹⁶);R¹⁶ represents, on each occasion when used herein, C₁₋₆ (C₁₋₃) alkyloptionally substituted by one or more fluoro atoms (so forming forexample a —CHF₂ or, preferably a —CF₃ group).

Further compounds of formula I that may be mentioned include those inwhich:

at least one of R¹ to R⁵, when present, represents halo, —R⁷, —CF₃, —CN,—C(O)R⁷, —C(O)OR⁷, —C(O)—N(R^(7a))R^(7b), —N(R⁷)₃ ⁺, —SR⁷, —OR⁷ or—NH(O)R⁷, or any two of R¹ to R⁵ which are adjacent to each other areoptionally linked to form, along with two atoms of the essential benzenering in the compound of formula I, an aromatic or non-aromatic 3- to8-membered ring, optionally containing 1 to 3 heteroatoms selected fromO, S and N, which ring is itself optionally substituted by one or moresubstituents selected from halo, —R⁷, —OR⁷ and ═O.

Further compounds of formula I that may be mentioned include those inwhich:

at least one of R¹ to R⁵, when present, represents heteroaryl, —OR⁷,halo, —CF₃, —CN, —C(O)R⁷, —C(O)—N(R^(7a))R^(7b), —C(O)OR⁷, —N(R⁷)₃ ⁺ or—NH(O)R⁷, or any two of R¹ to R⁵ which are adjacent to each other areoptionally linked to form, along with two atoms of the essential benzenering in the compound of formula I, an aromatic or non-aromatic 3- to8-membered ring selected from 2,3-dihydrobenzo[1,4]dioxinyl ortetrahydroquinolinyl, which may optionally be substituted by one or morehalo atoms.

Further compounds of formula I that may be mentioned include those inwhich:

at least one of R¹ to R⁵, when present, represents heteroaryl, —OR⁷,halo, —CF₃, —CN, —C(O)R⁷, —C(O)OR⁷, —C(O)—N(R^(7a))R^(7b), —N(R⁷)₃ ⁺ or—NH(O)R⁷.

Yet further compounds of formula I that may be mentioned include thosein which:

at least one of R¹ to R⁵, when present, represents 4H-[1,2,4]-triazolyl,—OR⁷ (e.g. —OCH₃, or more preferably, —OCHF₂ or —OCF₃), or, morepreferably, —Cl, —F, —CF₃, —CN or —C(O)—N(R^(7a))R^(7b).

Yet further compounds of formula I that may be mentioned include thosein which:

at least one of R¹ to R⁵, when present, represents —OR⁷ or, morepreferably, —Cl, —F, —CF₃, —CN or —C(O)—N(R^(7a))R^(7b).

Compounds of formula I that may be mentioned include those in which:

R⁶ independently represents —C(O)NR^(15a)R^(15b) or, more preferably,cyano, —NO₂, —Br, —Cl, —F, —OR⁸, —NR⁹R¹⁰, —SR¹¹, —C(O)OR¹³, —C(O)R¹⁴,—S(O)₂NR^(15c)R^(15d), aryl or heteroaryl (which aryl and heteroarylgroups are themselves optionally and independently substituted by one ormore groups selected from halo and R¹⁶), or any two R⁶ groups which areadjacent to each other are optionally linked to form, along with twoatoms of the essential benzene ring in the compound of formula I,quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline,wherein the additional ring system of the quinoline,tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline moiety isitself optionally substituted by one or more substituents selected fromhalo, —R⁷, —OR⁷ and ═O.

Further compounds of formula I that may be mentioned include those inwhich:

R⁶ independently represents —C(O)NR^(15a)R^(15b) or, more preferably,—R⁵ or yet more preferably, cyano, —NO₂, —Br, —Cl, —F, —NR⁹R¹⁰, —SR¹¹,—C(O)OR¹³, —C(O)R¹⁴, —S(O)₂NR^(15c)R^(15d), aryl or heteroaryl (whicharyl and heteroaryl groups are themselves optionally and independentlysubstituted by one or more groups selected from halo and R¹⁶).

Yet further compounds of formula I that may be mentioned include thosein which:

R⁶ independently represents —C(O)NR^(15a)R^(15b), —R⁸, or, morepreferably, —CN, —NO₂, —Br, —Cl, —F, —OR⁸, —NR⁹R¹⁰—SR¹¹, —C(O)OR¹³ or—C(O)R¹⁴.

Yet further compounds of formula I that may be mentioned include thosein which:

R⁶ independently represents —R⁸ or, more preferably, —CN, —OCF₃, —NO₂,—Br, —Cl, —F, —OR⁸, —NR⁹R¹⁰ or —SR¹¹.

Yet further compounds of formula I that may be mentioned include thosein which:

R⁶ independently represents —CN, —CF₃, —OCF₃, —F or, most preferably—Cl.

Compounds of formula I that may be mentioned include those in which:

n represents 2 or, more preferably, 1.

Further compounds of formula I that may be mentioned include those inwhich:

m represents 1 or, more preferably, 0;p represents 1 or, more preferably, 0.

Further compounds of formula I that may be mentioned include those inwhich:

A₅ represents N or, more preferably, C(Cl) or C(H).

Further compounds of formula I that may be mentioned include those inwhich:

A₁ and A₃ independently represent N or, more preferably, C(H).

Further compounds of formula I that may be mentioned include those inwhich:

A₂ represents C(R²);A₁ and A₃ to A₅ independently represent C(H) or N.

Yet further compounds of formula I that may be mentioned include thosein which:

A₂ represents C(R²);R² represents —CF₃;A₁ and A₃ to A₅ independently represent C(H).

Further compounds of formula I that may be mentioned include those inwhich:

A₅ represents C(R⁵);A₁ to A₄ independently represent C(H) or N.

Yet further compounds of formula I that may be mentioned include thosein which:

A₅ represents C(R⁵);R⁵ represents —Cl;A₁ to A₄ independently represent C(H).

Compounds of formula I that may be mentioned include those in which:

D represents (ortho-,para-)dichlorophenyl.

Compounds of formula I that may be mentioned include those in which:

D represents para-chlorophenyl.

More preferred compounds of formula I include those of the examplesdescribed hereinafter.

Preferred compounds of formula I include:

-   i)    5-(3,4-dichlorophenyl)imino-4-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazolidin-3-one;-   ii)    5-(3,4-dichlorophenyl)imino-4-[(4-methoxyphenyl)methyl]-1,2,4-thiadiazolidin-3-one;-   iii)    4-[(4-chlorophenyl)methyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one;-   iv)    5-(3,4-dichlorophenyl)imino-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one;-   v)    5-(3,4-dichlorophenyl)imino-4-[(3-fluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one;-   vi)    5-(3,4-dichlorophenyl)imino-4-[phenyl)methyl]-1,2,4-thiadiazolidin-3-one;-   vii)    5-(3,4-dichlorophenyl)imino-4-phenethyl-1,2,4-thiadiazolidin-3-one;-   viii)    4-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thia-diaz-olidin-3-one;-   ix)    4-[2-(4-chlorophenyl)sulfanylethyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one;-   x)    3-[[(5-(3,4-dichlorophenyl)imino-3-oxo-1,2,4-thiadiazolidin-4-yl]methyl]-N-methylbenz-amide;-   xi)    5-[(6-chloro-3-pyridyl)imino]-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one;-   xii)    4-[[4-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]amino]benzo-nitrile;-   xiii)    4-[(3,4-difluorophenyl)methyl]-5-[4-(trifluoromethyl)phenyl]imino-1,2,4-thiadiazolidin-3-one;-   xiv)    4-[(3,4-difluorophenyl)methyl]-5-[4-(trifluoromethoxy)phenyl]imino-1,2,4-thiadiazolidin-3-one;-   xv)    3-[5-(3,4-dichlorophenyl)imino-3-oxo-1,2,4-thiadiazolidin-4-yl]methyl]benzonitrile;-   xvi)    5-(3,4-dichlorophenyl)imino-4-[[4-(1,2,4-triazol-1-yl)phenyl]methyl]-1,2,4-thiadiaz-olidin-3-one;-   xvii)    4-[1-(4-chlorophenyl)cyclopropyl]-5-(4-chlorophenyl)imino-1,2,4-thiadiazolidin-3-one;-   xviii)    5-[(4-chlorophenyl)methylimino]-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one;-   N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]benzamide;-   xix)    4-fluoro-N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]benzamide;-   xx)    2-(4-fluorophenyl)-N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]acetamide;-   xxi)    4-chloro-N-[2-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxii)    4-chloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxiii)    4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxiv)    4-chloro-N-[2-[2-(phenoxy)ethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxv)    4-chloro-N-[2-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxvi)    4-chloro-N-[2-[2-(4-chlorophenyl)sulfanylethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxvii)    3,4-dichloro-N-[2-[1-(4-fluorophenyl)cyclopropyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxviii)    3,4-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxix)    N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-4-methoxy-benzamide;-   xxx)    2,6-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxxi)    2,4-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxxii)    N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy)-benzamide;-   xxxiii)    N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-3,5-bis(trifluoromethyl)-benzamide;-   xxxiv)    3,4-difluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxxv)    2-chloro-6-fluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxxvi)    3,5-difluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;-   xxxvii)    5-(3,4-dichlorophenyl)imino-4-(2-phenoxyethyl)-1,2,4-thiadiazolidin-3-one;-   xxxviii)    5-(3,4-dichlorophenylamino)-2-(2-phenoxyethyl)-[1,2,4]thiadiazol-3-one;-   xxxix)    4-benzhydryl-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one;-   xl)    4-chloro-N-[4-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benzamide;-   xli)    4-chloro-N-[4-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benzamide;-   xlii)    4-chloro-N4-[3-oxo-4-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazolidin-5-ylidene]-benzamide;-   xliii)    N-4-[4-[(3-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-4-(trifluoromethyl)-benzamide;-   xliv)    N-[4-[(3-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-3,5-bis(trifluoro-methyl)benzamide;-   xlv)    N-[4-[(3,4-dichlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-3,4-difluoro-benzamide;-   xlvi)    1,5-(3,4-dichlorophenylamino)-2-(4-methoxybenzyl)-[1,2,4]thiadiazol-3-one;-   xlvii)    1,5-(3,4-dichlorophenylamino)-2-(4-chlorobenzyl)-[12,4]thiadiazol-3-one;-   xlviii)    1,5-(3,4-dichlorophenylamino)-2-(3,4-difluorobenzyl)-[1,2,4]thiadiazol-3-one;-   xlix)    1,5-(3,4-dichlorophenylamino)-2-(3-fluorobenzyl)-[1,2,4]thiadiazol-3-one;-   l) 1,5-(3,4-dichlorophenylamino)-2-(benzyl)-[1,2,4]thiadiazol-3-one;-   li) 5-(3,4-dichlorophenylamino)-2-phenethyl-[1,2,4]thiadiazol-3-one;-   lii)    2-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-5-[(3,4-dichlorophenyl)amino]-1,2,4-thiadiazol-3-one;-   liii)    2-[2-(4-chlorophenyl)sulfanylethyl]-5-[(3,4-dichlorophenyl)amino]-1,2,4-thiadiazol-3-one;-   liv)    3-[[5-[(4-chlorophenyl)amino]-3-oxo-1,2,4-thiadiazol-2-yl]methyl]-N-methyl-benzamide;-   lv)    5-[(6-chloro-3-pyridyl)amino]-2-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazol-3-one;-   lvi)    2-[(3,4-difluorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lvii)    2-[(3,4-difluorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lviii)    5-[(4-chlorophenyl)amino]-2-[1-(4-chlorophenyl)cyclopropyl]-1,2,4-thiadiazol-3-one;-   lix)    5-[(3,4-dichlorophenyl)methylamino]-2-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazol-3-one;-   lx)    3,4-dichloro-N-[4-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benz-amide;-   lxi)    2-[(4-methoxyphenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lxii)    2-[(4-chlorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lxiii)    2-[(3-fluorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lxiv)    2-[phenylethyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lxv)    2-[(4-methoxyphenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lxvi)    2-[(4-chlorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lxvii)    2-[(3-fluorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;-   lxviii)    2-[phenylethyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;    and-   lxix)    4-[[2-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]amino]benzonitrile.

Compound names were derived using the commercially available softwarepackage Autonom (brand of nomenclature software provided as an add-onfor use in the Symyx Draw 2.1™ office suite marketed by MDL InformationSystems).

Throughout this specification, structures may or may not be presentedwith chemical names. Where any question arises as to nomenclature, thestructure prevails. Where it is possible for a compound to exist as atautomer the depicted structure represents one of the possibletautomeric forms, wherein the actual tautomeric form(s) observed mayvary depending on environmental factors such as solvent, temperature orpH.

Compounds of formula I may be prepared in accordance with techniquesthat are well known to those skilled in the art, for example asdescribed hereinafter.

According to a further embodiment of the invention there is provided aprocess for the preparation of a compound of formula I, which processcomprises:

(i) for compounds of formula I wherein A represents S, cyclisation of acompound of formula IIa,

wherein A₁ to A₅, X, W and D are as hereinbefore defined, under reactionconditions known to those skilled in the art, for example in thepresence of a suitable bromine source (e.g. N-bromo succinimide orbromine) and a suitable solvent (e.g. methanol, ethanol, ethyl acetate)and at a suitable temperature (e.g. −10° C. to 80° C.) as described inCastro et al. (Bioorganic. Med. Chem. 2008, 16, 495-510) or Kaugars etal. (J. Org. Chem. 1979, 44(22), 3840-3843), or in the presence of asuitable base (e.g. sodium hydroxide) in a suitable solvent (e.g. watercontaining hydrogen peroxide (e.g. a 30% H₂O₂ solution in water)) and ata suitable temperature (e.g. −10° C. to 100° C.) as described in Castroet al. (ibid), Cho et al. (J. Heterocyclic Chem. 1991, 28, 1645-1649)and Encinas et al. (Eur. J. Org. Chem. 2007, 5603-5608);(ii) for compounds of formula I wherein A represents S, W represents—[CR^(x)R^(y)]_(m)— and m represents 1 or 2, reaction of a compound offormula III,

wherein A₁ to A₅ and X are as hereinbefore defined, with a compound offormula IV,

L₂-W¹-D  IV

wherein L₂ represents a suitable leaving group such as halo (e.g.chloro), W¹ represents —[CR^(x)R^(y)]_(m)— in which m represents 1, andD is as hereinbefore defined, under reaction conditions known to thoseskilled in the art, for example in the presence of a suitable base (e.g.NaH, NaOH, triethylamine, pyridine, another suitable base mentioned atprocess step or mixtures thereof) and solvent (e.g. pyridine (which mayserve as the base and solvent), DMF or dichloromethane (e.g. further inthe presence of water and, optionally, a phase transfer catalyst)) forexample at room temperature e.g. as described in Hurst, D. T.; Stacey,A. D., Nethercleft, M., Rahim, A., Harnden, M. R. Aust. J. Chem. 1998,41, 1221;(iii) for compounds of formula I wherein A represents S, W represents—[CR^(x)R^(y)]_(m)— and m represents 0, reaction of a compound offormula III as hereinbefore defined with a compound of formula V,

L₃-D  V

wherein L₃ is a suitable leaving group (e.g. halo) and D is ashereinbefore defined, under reaction conditions known to those skilledin the art, for example in the presence of a suitable base (e.g. atributyltin amine or cyclohexylamine and lithiumbis(trimethylsilyl)amide), a suitable catalyst (e.g.PdCl₂(P(o-toluoyl)₃)₂), a suitable solvent (e.g. toluene) and at asuitable temperature (e.g. from room temperature to 105° C.), e.g. asdescribed in Harwig et al. J. Am. Chem. Soc. (1994), 116, 5969-5970,Buchwald et al., J. Am. Chem. Soc. (1994), 116, 7901-7902 and Buchwaldet al. Org. Process Res. Dev. (2006) 10(4), 762-769;(iv) for compounds of formula I wherein A represents S, W represents—C(O)—[CR^(x)R^(y)]_(p)—, reaction of a compound of formula III ashereinbefore defined, with a compound of formula VI,

L₄-W²-D  VI

wherein L₄ is a suitable leaving group (e.g. halo) or —OH, W² represents—C(O)—[CR^(x)R^(Y)]_(p)—, and D is as hereinbefore defined, when L₄represents a suitable leaving group, under reaction conditions known tothose skilled in the art, for example in an appropriate solvent (e.g.toluene, xylenes, DCM, chloroform), optionally in the presence of anbase (e.g. pyridine, Hunig's base, triethylamine) and at reduced toelevated temperatures (e.g. from 0° C. to 140° C.) or when L₄ representsOH, under standard coupling reaction conditions, for example, in thepresence of a suitable coupling reagent (e.g. 1,1′-carbonyldiimidazole,N,N′-dicyclohexylcarbodiimide,1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (or hydrochloridethereof), N,N′-disuccinimidyl carbonate,benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate,benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate,bromo-tris-pyrrolidinophosphonium hexafluoro-phosphate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetra-fluorocarbonate) or 1-cyclohexylcarbodiimide-3-propyloxymethylpolystyrene, optionally in the presence of a suitable base (e.g. sodiumhydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine,pyridine, triethylamine, tributylamine, trimethylamine,dimethylaminopyridine, diisopropylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide,N-ethyldiisopropylamine, N-(methylpolystyrene)-4-(methylamino)pyridine,potassium bis(trimethylsilyl)-amide, sodium bis(trimethylsilyl)amide,potassium tert-butoxide, lithium diisopropylamide, lithium2,2,6,6-tetramethylpiperidine or mixtures thereof) and an appropriatesolvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane,chloroform, acetonitrile or dimethylformamide) and at reduced toelevated temperatures (e.g. from 0° C. to 140° C.);(v) for compounds of formula I wherein A represents S, Q is a bond and nis 0, 1 or 2, or Q is —O— or —S— and n is 1 or 2, reaction of a compoundof formula VII,

wherein W and D are as hereinbefore defined, with a compound of formulaVIII,

wherein A₁ to A₅, R^(x) and R^(y) are as hereinbefore defined, L₅ is asuitable leaving group (e.g. bromo, chloro, iodo) and either Q is a bondand n is 0, 1 or 2, or Q is —O— or —S— and n is 1 or 2, under reactionconditions known to those skilled in the art, for example in thepresence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine)and solvent (e.g. pyridine (which may serve as the base and solvent) DMFor dichloromethane (e.g. further in the presence of water and,optionally, a phase transfer catalyst)), for example at room temperaturee.g. as described in Hurst, D. T.; Stacey, A. D., Nethercleft, M., PRahim, A., Harnden, M. R. Aust. J. Chem. 1998, 41, 1221;(vi) for compounds of formula I wherein A represents S and W is—[CR^(x)CR^(y)]_(m)—, reaction of a compound of formula IX,

wherein L₆ represents a suitable leaving group (e.g. halo) and A₁ to A₅and X are as hereinbefore defined, with a compound of formula X,

H₂N—W-D  X

wherein W and D₁ to D₅ are as hereinbefore defined, under reactionconditions known to those skilled in the art, for example thosedescribed by Keilen et al (Acta Chemica Scandinavica 1988, B 42,363-366), e.g. in a suitable solvent (e.g. chloroform,methylenechloride), in the presence of a suitable base (e.g. Hunig'sbase, triethyl amine) and at a suitable temperature (e.g. roomtemperature to 150° C., such as less than <100° C.); and(vii) for compounds of formula I wherein B represents S, cyclisation ofa compound of formula IIa,

Compounds of formula IIa may be prepared by reaction of a compound offormula XI,

wherein A₁ to A₅ and X are as hereinbefore defined, with a compound offormula XII,

wherein W and D₁ to D₅ are as hereinbefore defined, under reactionconditions known to those skilled in the art, for example in a suitablesolvent (e.g. acetone, dimethylformamide or 20% dimethylformamide inacetonitrile) at a suitable temperature (e.g. from −10° C. to 50° C.)and in the absence of a base, e.g. as described in Castro et al.(Bioorganic. Med. Chem. 2008, 16, 495-510) or Kaugars et al. (J. Org.Chem. 1979, 44(22), 3840-3843). Alternatively, a compound of formula Imay be formed directly by allowing any product so formed to be directlytreated under reaction conditions such as those described hereinbefore(e.g. process step (i) above).

Compounds of formula IIb may be prepared by reaction of a compound offormula XI as hereinbefore described, with a compound of formula XIIunder reaction conditions known to those skilled in the art, for examplein a suitable solvent (e.g. acetone, dimethylformamide) at a suitabletemperature (e.g. from −10° C. to 50° C.) and in the presence of asuitable base (e.g. n-butyl lithium), e.g. as described in Castro et al.(Bioorganic. Med. Chem. 2008, 16, 495-510) or Kaugars et al. (J. Org.Chem. 1979, 44(22), 3840-3843). Alternatively, a compound of formula Imay be formed directly by allowing any product so formed to be directlytreated under reaction conditions such as those described hereinbefore(e.g. process step (vii) above).

Alternatively, compounds of formula IIb may be formed by the selectiveN-alkylation of N-(3-oxo-1,2,4-thiadiazolidin-5-ylidene) amide derivatesas described by Castro et al (Bioorganic. Med. Chem. 2008, 16, 495-510).

Compounds of formula IX may be prepared by reaction of a compound offormula III with NaNO₂ and a suitable halogen source (e.g. hydrochloricacid), under reaction conditions known to those skilled in the art, forexample such as those described in Foroumadi et al. (1999) Arzneim.Forsch. 49, 1035-1038 or Foroumadi et al. (2005) Arch. Pharm. Chem. LifeSci. 338, 112-116, for example in the presence of a suitable metal (e.g.copper powder).

Compounds of formula XI may be prepared by analogy to the methodsdescribed in Xu et al. (Tetrahedron Lett. 1998, 39, 1107-1110) andKatritsky et al. (ARKIVOC (Archive for Organic Chemistry) 2003 (viii)8-14).

For compounds of formula XII in which W represents —C(O)—, reaction of acompound of formula XIII,

or the corresponding acyl halide (e.g. acyl chloride), or derivativethereof, wherein D₁ to D₅ are as hereinbefore defined, with athiocyanate (e.g. an alkali metal thiocyanate, such as potassiumthiocyanate), under reaction conditions known to those skilled in theart, for example in the presence of a suitable solvent (such asacetone), as described in Cho et al, J. Heterocyclic Chem. 1991, 28,1645-1649).

Compounds of formulae III, IV, V, VI, VII, VIII, X and XIII are eithercommercially available, are known in the literature, or may be obtainedeither by analogy with the processes described herein (or processesdescribed in references contained herein), or by conventional syntheticprocedures, in accordance with standard techniques, from availablestarting materials using appropriate reagents and reaction conditions.

Substituents, such as R², R³ and R⁴ in final compounds of formula I (orprecursors thereto and other relevant intermediates) may be modified oneor more times, after or during the processes described above by way ofmethods that are well known to those skilled in the art. Examples ofsuch methods include substitutions, reductions (e.g. carbonyl bondreductions in the presence of suitable and, if necessary,chemoselective, reducing agents such as LiBH₄ or NaBH₄), oxidations,alkylations, acylations, hydrolyses, esterifications, andetherifications. The precursor groups can be changed to a different suchgroup, or to the groups defined in formula I, at any time during thereaction sequence.

Compounds of formula I may be isolated from their reaction mixturesusing conventional techniques.

It will be appreciated by those skilled in the art that, in theprocesses described above and hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.

The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be removed in accordance with techniques that arewell known to those skilled in the art and as described hereinafter. Forexample, protected compounds/intermediates described herein may beconverted chemically to unprotected compounds using standarddeprotection techniques.

The type of chemistry involved will dictate the need, and type, ofprotecting groups as well as the sequence for accomplishing thesynthesis.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

As used herein, the term “functional groups” means, in the case ofunprotected functional groups, hydroxy-, thiolo-, aminofunction,carboxylic acid and, in the case of protected functional groups, loweralkoxy, N—, O—, S— acetyl, carboxylic acid ester.

Medical and Pharmaceutical Uses

Compounds of formula I are indicated as pharmaceuticals. According to afurther embodiment of the invention there is provided a compound offormula I, or a pharmaceutically-acceptable salt or solvate, or apharmaceutically functional derivative thereof, for use as apharmaceutical.

Advantageously, compounds of formula I may be AMPK agonists, i.e. theymay activate AMPK. By ‘activate AMPK’, we mean that the steady statelevel of phosphorylation of the Thr-172 moiety of the AMPK-α subunit isincreased compared to the steady state level of phosphorylation in theabsence of the agonist. Alternatively, or in addition, we mean thatthere is a higher steady state level of phosphorylation of any otherproteins downstream of AMPK, such as acetyl-CoA carboxylase (ACC).

As the compounds of formula I may be AMPK activators, they may thereforebe useful in the treatment of diseases such as those described herein,especially cancer.

Compounds of formula I may reduce the rate of cell proliferation whentested in an assay using a human breast cancer cell line (e.g.MDA-MB-231). The compounds may thus possess a beneficial inhibitoryeffect on the ability of tumors of this type, and of cancers generally,to survive. Compounds of formula I may also reduce the rate of cellproliferation when tested in other cancer cells lines (e.g. any p53mutant or p53 null cell line) such as, but not limited to, MCF-7, PC-3,Jurkat, SK-OV-3, HL60, MV4-11, HT-29, K562, MDA-MB-231, HCT116 wt,A-549, DU-145, LOVO, HCT-116 and PANC-1, independent of p53 status.

Compounds of formula I are therefore indicated for the inhibition ofcell proliferation. Compounds of formula I are therefore indicated foruse in the treatment of cancer.

According to a further embodiment of the invention, there is providedthe use of a compound of formula I, or a pharmaceutically-acceptablesalt or solvate, or a pharmaceutically functional derivative thereof forthe manufacture of a medicament for the treatment of cancer.

The compounds of formula I may be useful in the treatment of bothprimary and metastatic cancers.

The term “cancer” will be understood by those skilled in the art toinclude one or more diseases in the class of disorders that ischaracterized by uncontrolled division of cells and the ability of thesecells to invade other tissues, either by direct growth into adjacenttissue through invasion, proliferation or by implantation into distantsites by metastasis.

In a preferred embodiment, compounds of formula I are capable ofinhibiting the proliferation of cancer cells. By “proliferation” weinclude an increase in the number and/or size of cancer cells.

Alternatively, or preferably in addition, compounds of formula I arecapable of inhibiting metastasis of cancer cells.

By “metastasis” we mean the movement or migration (e.g. invasiveness) ofcancer cells from a primary tumor site in the body of a subject to oneor more other areas within the subject's body (where the cells can thenform secondary tumors). Thus, in one embodiment the invention providescompounds and methods for inhibiting, in whole or in part, the formationof secondary tumors in a subject with cancer. It will be appreciated byskilled persons that the effect of a compound of formula I on“metastasis” is distinct from any effect such a compound may or may nothave on cancer cell proliferation.

Advantageously, compounds of formula I may be capable of inhibiting theproliferation and/or metastasis of cancer cells selectively.

By “selectively” we mean that the combination product inhibits theproliferation and/or metastasis of cancer cells to a greater extent thanit modulates the function (e.g. proliferation) of non-cancer cells.Preferably, the compound inhibits the proliferation and/or metastasis ofcancer cells only.

Compounds of formula I may be suitable for use in the treatment of anycancer type, including all tumors (non-solid and, preferably, solidtumors, such as carcinoma, adenoma, adenocarcinoma, blood cancer,irrespective of the organ). For example, the cancer cells may beselected from the group consisting of cancer cells of the breast, bileduct, brain, colon, stomach, reproductive organs, thyroid, hematopoieticsystem, lung and airways, skin, gallbladder, liver, nasopharynx, nervecells, kidney, prostate, lymph glands and gastrointestinal tract.Preferably, the cancer is selected from the group of colon cancer(including colorectal adenomas), breast cancer (e.g. postmenopausalbreast cancer), endometrial cancer, cancers of the hematopoietic system(e.g. leukemia, lymphoma, etc), thyroid cancer, kidney cancer,oesophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreaticcancer, gallbladder cancer, liver cancer and cervical cancer. Morepreferably, the cancer is selected from the group of colon, prostateand, particularly, breast cancer. Where the cancer is a non-solid tumor,it is preferably a hematopoietic tumor such as a leukemia (e.g. AcuteMyelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), AcuteLymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL).

Preferably, the cancer cells are breast cancer cells.

According to a further embodiment of the invention there is provided amethod of treatment of cancer, which method comprises the administrationof an effective amount of a compound of formula I, or apharmaceutically-acceptable salt or solvate, or a pharmaceuticallyfunctional derivative thereof, to a patient in need of such treatment.

Compounds of formula I may also be of use in the treatment of a disorderor condition ameliorated by the activation of AMPK.

Compounds of formula I may be suitable for use in the treatment ofside-effects caused by cancer (e.g. cachexia).

According to a further embodiment of the invention, there is providedthe use of a compound of formula I, or a pharmaceutically-acceptablesalt or solvate, or a pharmaceutically functional derivative thereof,for the manufacture of a medicament for the treatment of a disorder orcondition ameliorated by the activation of AMPK.

The terms “disorder or condition ameliorated by the activation of AMPK”will be understood by those skilled in the art to include, in additionto cancer, diabetes, hyperinsulinemia and associated conditions, acondition/disorder where fibrosis plays a role, sexual dysfunction,osteoporosis and neurodegenerative diseases.

Compounds of formula I may thus also be indicated for use in thetreatment of a disorder or a condition caused by, linked to, orcontributed to by, hyperinsulinemia.

The terms “disorder or condition caused by, linked to, or contributed toby, hyperinsulinemia” or “treatment of hyperinsulinemia or an associatedcondition” will be understood by those skilled in the art to includehyperinsulinemia and associated conditions, such as type 2 diabetes,glucose intolerance, insulin resistance, metabolic syndrome,dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, highblood pressure, obesity, fatty liver conditions, diabetic nephropathy,diabetic neuropathy, diabetic retinopathy, cardiovascular disease,atherosclerosis, cerebrovascular conditions such as stroke, systemiclupus erythematosus, neurodegenerative diseases such as Alzheimer'sdisease, and polycystic ovary syndrome. Other disease states includeprogressive renal disease such as chronic renal failure. Preferreddisorders include hyperinsulinemia and, particularly, type 2 diabetes.

Certain compounds of formula I may also have the additional advantagethat they exhibit partial agonist activity and may therefore be usefulin conditions, such as late type 2 diabetes, in which stimulation of theproduction of insulin is required. By “agonist activity”, we includedirect and indirect-acting agonists.

According to a further embodiment of the invention there is provided amethod of treatment of a disorder or condition ameliorated by theactivation of AMPK, which method comprises the administration of aneffective amount of a compound of formula I, or apharmaceutically-acceptable salt or solvate, or a pharmaceuticallyfunctional derivative thereof, to a patient in need of such treatment.An effective amount can be determined by a physician and will bedetermined for a specific patient by assessment of the patient'sclinical parameters including, but not limited to the stage of disease,age, gender and histology.

Compounds of formula I may thus also be of use in the treatment of acondition/disorder where fibrosis plays a role. Compounds of formula Imay also be useful in the treatment of sexual dysfunction (e.g. thetreatment of erectile dysfunction).

A condition/disorder where fibrosis plays a role includes (but is notlimited to) scar healing, keloids, scleroderma, pulmonary fibrosis(including idiopathic pulmonary fibrosis), nephrogenic systemicfibrosis, and cardiovascular fibrosis (including endomyocardialfibrosis), systemic sclerosis, liver cirrhosis, eye maculardegeneration, retinal and vitreal retinopathy, Crohn's/inflammatorybowel disease, post surgical scar tissue formation, radiation andchemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis.

Compounds of formula I may thus also be of use in the treatment ofosteoporosis.

Compounds of formula I may thus also be of use in the treatment ofinflammation.

Compounds of formula I may thus also be of use in the treatment ofsexual dysfunction.

Compounds of formula I may thus also be of use in the treatment of heartfailure.

Compounds of formula I may thus also be of use in the treatment ofneurodegenerative diseases (e.g. Alzheimer's disease, Parkinson'sdisease and Huntington's disease, amyotrophic lateral sclerosis,polyglutamine disorders, such as spinal and bulbar muscular atrophy(SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a numberof spinocerebellar ataxias (SCA)).

For the avoidance of doubt, in the context of the present invention, theterms “treatment”, “therapy” and “therapy method” include thetherapeutic, or palliative, treatment of patients in need of, as well asthe prophylactic treatment and/or diagnosis of patients which aresusceptible to, the relevant disease states.

“Patients” include mammalian (including human) patients.

The term “effective amount” refers to an amount of a compound, whichconfers a therapeutic effect on the treated patient (e.g. sufficient totreat or prevent the disease). The effect may be objective (i.e.measurable by some test or marker) or subjective (i.e. the subject givesan indication of or feels an effect).

In accordance with the invention, compounds of formula I may beadministered alone, but are preferably administered orally,intravenously, intramuscularly, cutaneously, subcutaneously,transmucosally (e.g. sublingually or buccally), rectally, transdermally,nasally, pulmonarily (e.g. tracheally or bronchially), topically, by anyother parenteral route, in the form of a pharmaceutical preparationcomprising the compound in a pharmaceutically acceptable dosage form.Preferred modes of delivery include oral, intravenous, cutaneous orsubcutaneous, nasal, intramuscular, or intraperitoneal delivery.

Compounds of formula I will generally be administered as apharmaceutical formulation in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier, which may be selected with dueregard to the intended route of administration and standardpharmaceutical practice. Such pharmaceutically acceptable carriers maybe chemically inert to the active compounds and may have no detrimentalside effects or toxicity under the conditions of use. Suitablepharmaceutical formulations may be found in, for example, Remington TheScience and Practice of Pharmacy, 19th ed., Mack Printing Company,Easton, Pa. (1995). For parenteral administration, a parenterallyacceptable aqueous solution may be employed, which is pyrogen free andhas requisite pH, isotonicity, and stability. Suitable solutions will bewell known to the skilled person, with numerous methods being describedin the literature. A brief review of methods of drug delivery may alsobe found in e.g. Langer, Science 249, 1527 (1990).

Otherwise, the preparation of suitable formulations may be achievednon-inventively by the skilled person using routine techniques and/or inaccordance with standard and/or accepted pharmaceutical practice.

Another aspect of the present invention includes a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I, or a pharmaceutically-acceptable salt or solvate, or apharmaceutically functional derivative thereof, in combination with apharmaceutically acceptable excipient, such as an adjuvant, diluent orcarrier.

The amount of compound of formula I in the formulation will depend onthe severity of the condition, and on the patient, to be treated, aswell as the compound(s) which is/are employed, but may be determinednon-inventively by the skilled person.

Depending on the disorder, and the patient, to be treated, as well asthe route of administration, compounds of formula I may be administeredat varying therapeutically effective doses to a patient in need thereof.

However, the dose administered to a mammal, particularly a human, in thecontext of the present invention should be sufficient to effect atherapeutic response in the mammal over a reasonable timeframe. Oneskilled in the art will recognize that the selection of the exact doseand composition and the most appropriate delivery regimen will also beinfluenced by inter alia the pharmacological properties of theformulation, the nature and severity of the condition being treated, andthe physical condition and mental acuity of the recipient, as well asthe potency of the specific compound, the age, condition, body weight,sex and response of the patient to be treated, and the stage/severity ofthe disease.

Administration may be continuous or intermittent (e.g. by bolusinjection). The dosage may also be determined by the timing andfrequency of administration. In the case of oral or parenteraladministration the dosage can vary from about 0.01 mg to about 1000 mgper day of a compound of formula I (or, if employed, a correspondingamount of a pharmaceutically acceptable salt or prodrug thereof).

In any event, the medical practitioner, or other skilled person, wilt beable to determine routinely the actual dosage, which will be mostsuitable for an individual patient. The above-mentioned dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

The compounds of formula I may be used or administered in combinationwith one or more additional drugs useful in the treatment of cancer, incombination therapy.

According to a further embodiment of the invention, there is provided acombination product comprising:

(A) a compound of formula I; and(B) another therapeutic agent useful in the treatment of cancer,wherein each of components (A) and (B) is formulated in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.

Other therapeutic agents useful in the treatment of cancer includestandard cancer therapies, such as cytostatica, irradiation andphotodynamic therapy, among others known to the physician.

It is preferred that the other therapeutic agent is a cytostatic (suchas a taxane (e.g. docetaxel and, particularly, paclitaxel) orpreferably, a platin (e.g. cisplatin and carboplatin) or ananthracycline (e.g. doxorubicin)) or an angiogenesis inhibitor, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative of either of these. However, the other therapeutic agent mayalso be selected from:

-   (i) tamoxifen, or a pharmaceutically-acceptable salt, solvate or    pharmaceutically functional derivative thereof;-   (ii) an aromatase inhibitor (i.e. a compound that blocks the    production of estrogen from adrenal androgens via the aromatase    pathway in peripheral tissues), or a pharmaceutically-acceptable    salt, solvate or pharmaceutically functional derivative thereof.    Preferred AIs include anastrozole, letrozole and exemastane;-   (iii) trastuzumab (Herceptin), or another antibody that is useful in    the treatment of cancer, such as bevacizumab, cetuximab or    panitumumab;-   (iv) a tyrosine kinase inhibitor (i.e. a compound that blocks (or is    capable of blocking), to a measurable degree, the    autophosphorylation of tyrosine residues, thereby preventing    activation of the intracellular signalling pathways in tumor cells),    or a pharmaceutically-acceptable salt, solvate or pharmaceutically    functional derivative thereof. Preferred TKIs include inhibitors of    the vascular endothelial growth factor (VEGF) family, and/or the    HER-family of TKs, such as HER-1/Human Epidermal Growth Factor    (EGFR; erbB1), HER3 (erbB3), HER4 (erbB4) and, more particularly,    HER2 (erbB2). Preferred TKIs thus include imatinib, gefitinib,    erlotinib, canertinib, sunitinib, zactima, vatalanib, sorafenib,    leflunomide and, particularly, lapatinib;-   (v) a glitazone, such as troglitazone, pioglitazone and    rosiglitazone, or a pharmaceutically-acceptable salt, solvate or    pharmaceutically functional derivative thereof;-   (vi) a biguanide such as phenformin, buformin, or, most preferably,    metformin, or a pharmaceutically-acceptable salt, solvate or    pharmaceutically functional derivative thereof;-   (vii) a statin, such as fluvastatin, simvastatin, rosuvastatin,    pravastatin, atorvastatin and, particularly, lovastatin, or a    pharmaceutically-acceptable salt, solvate or pharmaceutically    functional derivative thereof;-   (viii) an inhibitor of activity of the mammalian target of rapamycin    (mTOR), such as rapamycin, or a pharmaceutically-acceptable salt,    solvate or pharmaceutically functional derivative thereof;-   (ix) an oligomycin, such as oligomycin A, oligomycin B, oligomycin    C, oligomycin D (rutamycin A), oligomycin E, oligomycin F, rutamycin    B, 44-homooligomycin A and 44-homooligomycin B, or a    pharmaceutically-acceptable salt, solvate or pharmaceutically    functional derivative thereof;-   (x) AICAR (aminoimidazole carboxamide ribonucleotide), or a    pharmaceutically-acceptable salt, solvate or pharmaceutically    functional derivative thereof;-   (xi) a peroxisome proliferator-activated receptor (PPAR) agonist    (which also include thiazolidinediones), or a    pharmaceutically-acceptable salt, solvate or pharmaceutically    functional derivative thereof;-   (xii) A-769662, or a pharmaceutically-acceptable salt, solvate or    pharmaceutically functional derivative thereof;-   (xiii) D942    (5-(3-(4-(2-(4-Fluorophenyl)ethoxy)-phenyl)propyl)furan-2-carboxylic    acid), or a pharmaceutically-acceptable salt, solvate or    pharmaceutically functional derivative thereof;-   (xiv) AM251 (a CB, receptor antagonist), or a    pharmaceutically-acceptable salt, solvate or pharmaceutically    functional derivative thereof;-   (xv) a SIRT1 activator, such as resveratrol and SRT-1720    (N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxal-ine-2-carboxamide),    or a pharmaceutically-acceptable salt, solvate or pharmaceutically    functional derivative thereof; and/or-   (xvi) salidroside, or a pharmaceutically-acceptable salt, solvate or    pharmaceutically functional derivative thereof.

By “agonist” we include direct and indirect-acting agonists.

It has recently been suggested in the literature (see, for example, Mol.Cancer. Ther., 5, 430 (2006), Cancer Res., 66, 10269 (2006) and Int. J.Cancer, 118, 773 (2006)) that the above mentioned compound classes (v)to (vii) may be used in the treatment of cancer, as described herein.

When the other therapeutic agent is (particularly) in category (i) or(ii) above, combination products according to embodiments of theinvention are particularly useful in the treatment of ER-positivecancers and/or early-stage breast cancers, for example in adjuvanttherapy (i.e. reducing the risk of the cancer coming back aftersurgery), in neo-adjuvant therapy (before surgery, to shrink a largebreast cancer so that a lumpectomy is possible), in the control ofbreast cancers that have come back after initial treatment, or in thecontrol of breast cancers that cannot be removed when first diagnosed.Such combination products according to embodiments of the invention arealso particularly useful in the treatment of patients at a high risk ofbreast cancer.

When the other therapeutic agent is (particularly) in category (iii) or(iv) above, combination products according to embodiments of theinvention are particularly useful in the treatment of HER2-positivecancers.

Pharmaceutically-acceptable salts, solvates or pharmaceuticallyfunctional derivatives of any of the compounds listed in categories (i),(ii) and (iv) to (xvi) above are as described hereinbefore. Inparticular, when the other therapeutic agent is tamoxifen, preferredpharmaceutically-acceptable salts include those of citric acid, when theother therapeutic agent is imatinib, preferredpharmaceutically-acceptable salts include mesylate salts and when theother therapeutic agent is sunitinib, preferredpharmaceutically-acceptable salts include maleate salts.

Combination products as described herein provide for the administrationof compound of formula I in conjunction with the other therapeuticagent, and may thus be presented either as separate formulations,wherein at least one of those formulations comprises compound of formulaI, and at least one comprises the other therapeutic agent, or may bepresented (i.e. formulated) as a combined preparation (i.e. presented asa single formulation including compound of formula I and the othertherapeutic agent).

Thus, there is further provided:

(1) pharmaceutical formulations including a compound of formula I;another therapeutic agent useful in the treatment of cancer; and apharmaceutically-acceptable adjuvant, diluent or carrier; and(2) kits of parts comprising components:

-   -   (a) a pharmaceutical formulation including a compound of formula        I, in admixture with a pharmaceutically-acceptable adjuvant,        diluent or carrier; and    -   (b) a pharmaceutical formulation including another therapeutic        agent useful in the treatment of cancer, in admixture with a        pharmaceutically-acceptable adjuvant, diluent or carrier,        which components (a) and (b) are each provided in a form that is        suitable for administration in conjunction with the other.

Components (a) and (b) of the kits of parts described herein may beadministered simultaneously or sequentially.

According to a further embodiment of the invention, there is provided amethod of making a kit of parts as defined above, which method comprisesbringing component (a), as defined above, into association with acomponent (b), as defined above, thus rendering the two componentssuitable for administration in conjunction with each other.

By bringing the two components “into association with” each other, weinclude that components (a) and (b) of the kit of parts may be:

(i) provided as separate formulations (i.e. independently of oneanother), which are subsequently brought together for use in conjunctionwith each other in combination therapy; or(ii) packaged and presented together as separate components of a“combination pack” for use in conjunction with each other in combinationtherapy.

Thus, there is further provided a kit of parts comprising:

(I) one of components (a) and (b) as defined herein; together with(II) instructions to use that component in conjunction with the other ofthe two components.

The kits of parts described herein may comprise more than oneformulation including an appropriate quantity/dose of compound offormula I, and/or more than one formulation including an appropriatequantity/dose of the other therapeutic agent, in order to provide forrepeat dosing. If more than one formulation (comprising either activecompound) is present, such formulations may be the same, or may bedifferent in terms of the dose of either compound, chemicalcomposition(s) and/or physical form(s).

With respect to the kits of parts as described herein, by“administration in conjunction with”, we include that respectiveformulations comprising compound of formula I and the other therapeuticagent are administered, sequentially, separately and/or simultaneously,over the course of treatment of the relevant condition.

Thus, in respect of the combination product according to embodiments ofthe invention, the term “administration in conjunction with” includesthat the two components of the combination product (compound of formulaI and the other therapeutic agent) are administered (optionallyrepeatedly), either together, or sufficiently closely in time, to enablea beneficial effect for the patient, that is greater, over the course ofthe treatment of the relevant condition, than if either a formulationcomprising compound of formula I, or a formulation comprising the othertherapeutic agent, are administered (optionally repeatedly) alone, inthe absence of the other component, over the same course of treatment.Determination of whether a combination provides a greater beneficialeffect in respect of, and over the course of treatment of, a particularcondition will depend upon the condition to be treated or prevented, butmay be achieved routinely by the skilled person.

Further, in the context of a kit of parts according to embodiments ofthe invention, the term “in conjunction with” includes that one or otherof the two formulations may be administered (optionally repeatedly)prior to, after, and/or at the same time as, administration with theother component. When used in this context, the terms “administeredsimultaneously” and “administered at the same time as” include thatindividual doses of compound of formula I and the other therapeuticagent are administered within 48 hours (e.g. 24 hours) of each other.

The compounds/combinations/methods/uses described herein may have theadvantage that, in the treatment of the conditions described herein,they may be more convenient for the physician and/or patient than, bemore efficacious than, be less toxic than, have better selectivity, havea broader range of activity than, be more potent than, produce fewerside effects than, or may have other useful pharmacological propertiesover, similar compounds, combinations, methods (treatments) or usesknown in the prior art for use in the treatment of those conditions orotherwise, for example over the compounds disclosed in internationalpatent applications WO 2007/010273 and WO 2007/010281.

Further, such advantages may stem from the compounds of formula I beingAMPK activators (e.g. especially where it is stated that the compoundsdescribed herein may have better selectivity, and may produce fewer sideeffects, e.g. gastrointestinal side effects).

Preferred, non-limiting examples which embody certain aspects of theinvention will now be described, with reference to the followingfigures:

FIG. 1, which shows the effect of the compound of Example 1 or thecompound of Example 2c on AMPK phosphorylation. After starvation of PC3cells in serum-free medium for 24 h, 0.3, 0.6, 1.2 and 2.5 μM of thecompound of Example 1 or the compound of Example 2c was added andincubated for an additional 4 h. The Figure provides representativeimmunoblots of AMPK phosphorylation by the compound of Example 1 or thecompound of Example 2c. The compound of Example 1 and the compound ofExample 2c stimulates AMPK phosphorylation in PC3 cells.

FIG. 2, which shows the effect of the compound of selected compounds ofthe examples on AMPK phosphorylation in comparison to total AMPK levels,and on acetyl co-enzyme A (acetyl-CoA) carboxylase phosphorylation (asubstrate of AMPK). After starvation of PC3 cells in serum-free mediumfor 16 h, 1 and 5 μM of the selected compounds were added and incubatedfor an additional 4 h. The Figure provides representative immunoblots ofthe total level of AMPK (Pan-AMPK) and the level of AMPK and acetyl-CoAcarboxylase phosphorylation by the selected compounds of the examples.The selected compounds of the examples stimulate AMPK phosphorylation inPC3 cells and induce the phosphorylation of acetyl-CoA carboxylase.

FIG. 3, which shows that the compound of Example 1 and 2c can reducePP2C-α1 mediated dephosphorylation of AMPK. The compounds were tested inthe assay at concentrations of 2.5, 5 and 10 μM (as depicted in thefigure).

EXAMPLES

The invention is illustrated by the following examples, in which thefollowing abbreviations may be employed:

BrdU 5-bromo-2-deoxyuridinenBuLi N-butyl lithiumDCM dichloromethaneDMF dimethylformamideDMSO dimethylsulfoxideES electro sprayEt₂O diethyl etherEtOAc ethyl acetateEtOH ethanolLC liquid chromatographyMeOH methanolMS mass spectrometryMTBE methyl tert-butyl etherNMR nuclear magnetic resonanceTHF tetrahydrofuran

Where no preparative routes are included, the relevant intermediate iscommercially available (e.g. from Chemical Diversity, San Diego, Calif.,USA or other available commercial sources).

General Procedures

LC-MS was performed on a Sciex API 150 LC/ES-MS equipped with an ACE 3C8 column (30×3.0 mm) using a flow of 1 mL/min. Two gradient systems ofacetonitrile in water (with 0.1% TFA) are used for elution: A) 5-100%under 10 min, then 2 min 100% isocratic or B) 90-100% under 2 min, then2 min 100% isocratic. Direct inlet ES-MS was also performed on a BrukerEsquire LC/ES-MS. ¹H nuclear magnetic resonance was recorded on a BrukerAvance DRX 400 spectrometer at 400.01 MHz using residual solvent asinternal standard.

General Procedure for Synthesis of Benzoyl Isothiocyanates from BenzoylChlorides

To a mixture of the benzoyl chloride (5 mmol) and tributylamine bromide(0.15 mmol) in toluene (10 mL) was added Potassium isothiocyanate (13mmol) in water (10 mL) at rt. The mixture was stirred at r.t for 18 h.The phases were separated and the aq. phase was extracted with toluene(2×20 mL). The combined organic phases were dried over MgSO4, filteredthrough a short plug of silica gel and evaporated to yield the benzoylisothiocyanate with high purity according to ¹H NMR. The material isused in the next step without further purification.

Example 15-(3,4-dichlorophenyl)imino-4-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazolidin-3-one

(i)1-[(3,4-dichlorophenyl)carbamothioyl]-1-[[3-(trifluoromethyl)phenyl]methyl]urea

To a solution of 3-trifluoromethyl benzyl urea (218 mg, 1 mmol) in dryTHF (2 mL) under nitrogen was added dropwise n-BuLi (2.5 M in hexane,0.4 mL). The mixture was stirred at RT for 30 min and then3,4-dichlorophenyl isothiocyanate (204 mg, 1 mmol) in dry THF (2 mL) wasadded dropwise. HPLC analysis after 5 min revealed complete reaction tothe expected product. Saturated NaHCO₃ (5 mL) and Et₂O (15 mL) wereadded and the phases were separated. The aqueous phase was extractedwith Et₂O (2×15 mL). The combined organic phases were washed with brine(5 mL) and were dried over MgSO₄. Concentration in vacuo gave 412 mg ofa yellow oil. Purification by flash chromatography (silica, 20-30% EtOAcin n-hexane) gave 193 mg (46%) of pure product according to ¹H NMR.

MS: m/z: 422 (M+H); Purity (HPLC): 95.2%; ¹H NMR (500 MHz, Chloroform-d)δ ppm 13.34 (s, 1H) 7.81 (s, 1H) 7.54-7.65 (m, 4H) 7.47 (s, 2H) 5.82 (s,2H) 5.02 (br. s., 2 H)

(ii)5-(3,4-dichlorophenyl)imino-4-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazolidin-3-one

Bromine (16 mg in 0.5 mL of EtOH) was added dropwise to a solution of1-[(3,4-dichlorophenyl)carbamothioyl]-1-[[3-(trifluoromethyl)phenyl]methyl]urea(42 mg, 0.1 mmol) in 0.5 mL EtOH at 0° C. HPLC-MS analysis revealedalmost complete conversion to product after 30 min of stirring. Thereaction was worked up after 1.5 h. Water (3 mL) was added and theresulting aqueous phase was extracted with Et₂O (3×15 mL). The combinedorganic phases were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to yield 43.5 mg of crude material (approximately90% purity). The material was purified by preparative HPLC (basicconditions) XTerra Prep MS C18 5 mm 19×50 mm column, flow 25 ml/min, 50mM pH10 NH4HCO3/ACN, 5-97% ACN in 6 min, fractions collected based onUV-signal (254 nm) to give the product in 21.7 mg (52%). HPLC purity:98.5%, MS: m/z: 420 (M+H), ¹H NMR (500 MHz, Chloroform-d) 8 ppm 7.81 (s,1 H) 7.70 (d, J=7.81 Hz, 1H) 7.60 (d, J=7.81 Hz, 1H) 7.49 (t, J=7.69 Hz,1H) 7.40 (d, J=8.55 Hz, 1H) 7.06 (d, J=2.44 Hz, 1H) 6.79 (dd, J=8.55,2.44 Hz, 1H) 5.04 (s, 2H).

Example 2

The following compounds were (compounds (c) and (e)), or may be preparedusing procedures described in the specification above.

a)5-(3,4-dichlorophenyl)imino-4-[(4-methoxyphenyl)methyl]-1,2,4-thiadiazolidin-3-one

b)4-[(4-chlorophenyl)methyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one

c)5-(3,4-dichlorophenyl)imino-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one

¹H NMR (500 MHz, Methanol-d₄) 8 ppm 7.48 (d, J=8.55 Hz, 1H) 7.39 (ddd,J=11.35, 7.81, 1.83 Hz, 1H) 7.22-7.31 (m, 2H) 7.15 (d, J=2.44 Hz, 1H)6.92 (dd, J=8.55, 2.69 Hz, 1H) 4.97 (s, 2H). ESI MS m/z=388 [M+H]⁺;

d)5-(3,4-dichlorophenyl)imino-4-[(3-fluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one

e)5-(3,4-dichlorophenyl)imino-4-[phenyl)methyl]-1,2,4-thiadiazolidin-3-one

¹H NMR (500 MHz, Methanol-d₄) δ ppm 7.47 (d, J=8.55 Hz, 1H) 7.45 (d,J=7.32 Hz, 2H) 7.35 (t, J=7.32 Hz, 2H) 7.28-7.33 (m, 1H) 7.14 (d, J=2.44Hz, 1H) 6.92 (dd, J=8.55, 2.44 Hz, 1H) 5.01 (s, 2H). ESI MS m/z=352[M+H]⁺;

f) 5-(3,4-dichlorophenyl)imino-4-phenethyl-1,2,4-thiadiazolidin-3-one

g)4-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiaz-olidin-3-one

h)4-[2-(4-chlorophenyl)sulfanylethyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one

i)3-[[(5-(3,4-dichlorophenyl)imino-3-oxo-1,2,4-thiadiazolidin-4-yl]methyl]-N-methylbenz-amide

j)5-[(6-chloro-3-pyridyl)imino]-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one

k)4-[[4-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]amino]benzo-nitrile

l)4-[(3,4-difluorophenyl)methyl]-5-[4-(trifluoromethyl)phenyl]imino-1,2,4-thiadiazolidin-3-one

m)4-[(3,4-difluorophenyl)methyl]-5-[4-(trifluoromethoxy)phenyl]imino-1,2,4-thiadiazolidin-3-one

n)3-[5-(3,4-dichlorophenyl)imino-3-oxo-1,2,4-thiadiazolidin-4-yl]methyl]benzonitrile

o)5-(3,4-dichlorophenyl)imino-4-[[4-(1,2,4-triazol-1-yl)phenyl]methyl]-1,2,4-thiadiaz-olidin-3-one

p)4-[1-(4-chlorophenyl)cyclopropyl]-5-(4-chlorophenyl)imino-1,2,4-thiadiazolidin-3-one

and

q)5-[(4-chlorophenyl)methylimino]-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one

Example 3N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]benzamide

(i) N-[3-(3-Trifluoromethylbenzyl)-ureidocarbothioyl]-benzamide

(3-Trifluoromethyl-benzyl)-urea (218 mg; 1.0 mmol) and 163 mg (1.0 mmol)benzoylisothiocyanate were dissolved in acetone and the mixture washeated to reflux. After 18 h of reflux HPLC-MS revealed almost completeconversion to expected product in a very clean reaction. The solvent wasevaporated and the residue was dissolved in EtOAc (40 mL). Wash with 2MHCl (5 mL), water (2×5 mL) and brine (5 mL), and the organic phase wasdried over MgSO4 and concentrated in vacuo to give 347 mg of a lightyellow solid. HPLC-MS indicates a purity of approximately 90%.

Part of the crude material was used in the next step without furtherpurification.

1H NMR (500 MHz, Methanol-d4) δ ppm 7.95 (dd, J=8.30, 1.22 Hz, 2H) 7.68(d, J=0.98 Hz, 1H) 7.65 (dd, J=8.79, 7.57 Hz, 2H) 7.59 (d, J=7.08 Hz,1H) 7.51-7.57 (m, 3H) 4.63 (s, 2H).

(ii)N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]benzamide

Bromine (17 mg in 0.5 mL of EtOH, 0.1 mmol) was added dropwise to asolution of 40 mg (0.1 mmol)N-[3-(3-trifluoromethylbenzyl)-ureidocarbothioyl]-benzamide (from step(i) above) in 3.5 mL EtOH at rt. HPLC-MS indicated complete reactionafter 15 min. The solvent was removed in vacuo to give 51 mg of anorange solid. The solid was trituated with EtOAc to yield 25 mg (63%) ofpure product as an off-white solid after drying.

30 MS: [M+H]: 380.0, HPLC purity: 99%.

1H NMR (500 MHz, Methanol-d4) δ ppm 8.11 (dd, J=8.42, 1.10 Hz, 2H) 7.70(s, 1H) 7.63-7.69 (m, 3H) 7.57-7.62 (m, 1H) 7.55 (t, J=7.69 Hz, 2H) 4.97(s, 2H).

Example 4

The following compounds were (compounds (a) to (f) and (j) to (r)) ormay be prepared using procedures described in the specification above.

a)4-fluoro-N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]benzamide

MS: [M+H]: 398.0, HPLC purity: 100%, 1H NMR (500 MHz, Methanol-d₄) δppm: 8.19 (dd, J=8.79, 5.37 Hz, 2H) 7.69 (s, 1H) 7.62-7.67 (m, 2H)7.56-7.62 (m, 1H) 7.26 (t, J=8.79 Hz, 2H) 4.94 (s, 2H);

b)2-(4-fluorophenyl)-N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]acetamide

MS: [M+H]: 412, HPLC purity: 100%, 1H NMR (500 MHz, Methanol-d₄) δ ppm7.64 (s, 1 H) 7.60-7.63 (m, 1H) 7.57-7.60 (m, 1H) 7.53-7.57 (m, 1H) 7.31(dd, J=8.55, 5.37 Hz, 2H) 7.06 (t, J=8.79 Hz, 2H) 4.95 (s, 2H) 3.86 (s,2H);

c)4-chloro-N-[2-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS: [M+H]: 382.0, HPLC purity: 100%, 1H NMR (500 MHz, DMSO-d₆) δ ppm8.10 (d, J=8.79 Hz, 2H) 7.62 (d, J=8.30 Hz, 2H) 7.38-7.49 (m, 2H) 7.21(ddd, J=6.23, 4.15, 2.08 Hz, 1H) 4.78 (s, 2H)

d)4-chloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS: [M+H]: 364.0, HPLC purity: 100%, 1H NMR (500 MHz, DMSO-d₆) δ ppm8.10 (d, J=8.55 Hz, 2H) 7.62 (d, J=8.79 Hz, 2H) 7.41 (dd, J=8.67, 5.49Hz, 2H) 7.21 (t, J=8.91 Hz, 2H) 4.78 (s, 2H);

e)4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS: [M+H]: 380.0, HPLC purity: 100%, 1H NMR (500 MHz, DMSO-d⁶) δ ppm8.10 (d, J=8.55 Hz, 2H) 7.63 (d, J=8.55 Hz, 2H) 7.44 (d, J=8.55 Hz, 2H)7.38 (d, J=8.55 Hz, 2 H) 4.79 (s, 2H);

f)4-chloro-N-[2-[2-(phenoxy)ethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS: [M+H]: 377.0, HPLC purity: 100%, 1H NMR (500 MHz, DMSO-d6) d ppm8.12 (d, J=8.55 Hz, 2H) 7.63 (d, J=8.79 Hz, 2H) 7.30 (dd, J=8.55, 7.32Hz, 2H) 6.93-6.99 (m, 3H) 4.20 (t, J=5.00 Hz, 2H) 3.97 (t, J=5.01 Hz,2H);

g)4-chloro-N-[2-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

h)4-chloro-N-[2-[2-(4-chlorophenyl)sulfanylethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

i)3,4-dichloro-N-[2-[1-(4-fluorophenyl)cyclopropyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

j)3,4-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.78 (s, 2H) 7.18-7.24 (m, 2H) 7.38-7.43(m, 2H) 7.83 (d, J=8.30 Hz, 1H) 8.02 (dd, J=8.55, 1.95 Hz, 1H) 8.24 (d,J=1.95 Hz, 1H);

-   k)    N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-4-methoxy-benzamide

MS:[M+H]: 360, HPLC purity: 95%;

l)2,6-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS:[M+H]: 398, HPLC purity: 95%;

m)2,4-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS:[M+H]: 398, HPLC purity: 98%

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.80 (s, 2H) 7.19-7.24 (m, 2H) 7.39-7.44(m, 2H) 7.60 (dd, J=8.42, 2.08 Hz, 1H) 7.79 (d, J=1.71 Hz, 1H) 7.91 (br.s., 1H) 13.71 (br. s., 1H);

n)N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy)-benzamide

MS:[M+H]: 414, HPLC purity: 100%;

o)N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-3,5-bis(trifluoromethyl)-benzamide

MS:[M+H]: 466, HPLC purity: 95%;

p)3,4-difluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS:[M+H]: 366, HPLC purity: 100%;

q)2-chloro-6-fluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS:[M+H]: 382, HPLC purity: 100%; and

r)3,5-difluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide

MS:[M+H]: 366, HPLC purity: 95%.

Compounds 4j-4r were synthesized from a compound of formula III byreaction with compounds of formula IV wherein L₂ is chlorine and W¹ is—C(O)— (Substituted benzoylchloride).

Compounds 4j-4r were synthesized as a small compound library in thefollowing way: 5-Amino-2-(4-fluoro-benzyl)-[1,2,4]thiadiazol-3-one andpyridine were mixed in 400 μl of acetonitrile. The acid chloride in 100μl of acetonitrile was added. The reactions were stirred overnight. 50μl 2 M KOH was added to hydrolyse the disubstituted biproduct. After 1day was the reactions acidified with 100 μl of TFA, diluted to 2 ml withDMSO/methanol/water and purified with reversed phase chromatography (ACEC8, 5 μm, 21×50 mm, flow 25 ml/min, gradient: water+0.1%TFA/acetonitrile over 6 minutes).

Example 5 a)5-(3,4-dichlorophenyl)imino-4-(2-phenoxyethyl)-1,2,4-thiadiazolidin-3-one;and b)5-(3,4-Dichloro-phenylamino)-2-(2-phenoxy-ethyl)-[1,2,4]thiadiazol-3-one

(i)(2-Phenoxy-ethyl)-urea

2-Phenoxyethyl amine (137 mg, 1 mmol) and urea (300 mg, 5 mmol) wereplaced in a 2 mL microwave vial. Conc. HCl (200 μL) and water (500 μL)were added and the mixture was heated to 150° C. for 30 min undermicrowave irradiation. After cooling the vial was full of whiteprecipitate. The solid was collected by filtration, and was washed withseveral portions of water. After drying in a vacuum dessicator 167 mg(93%) of product as a white crystalline material was isolated. HPLC-MSrevealed that the product consisted of a mixture of 67% product and 33%dialkylated product. Purification by flash chromatography: (silica, 4-5%MeOH in CH2Cl2) gave 79 mg (44%) of pure product as a white solid.

1H NMR (500 MHz, Methanol-d4) δ ppm 7.28 (dd, J=8.91, 7.20 Hz, 2H)6.90-6.99 (m, 3H) 4.02 (t, J=5.37 Hz, 2H) 3.51 (t, J=5.37 Hz, 2H)

(ii) (a) 1-[(3,4-dichlorophenyl)carbamothioyl]-1-(2-phenoxyethyl)urea(b) 1-[(3,4-dichlorophenyl)carbamothioyl]-1-(2-phenoxyethyl)urea

To a solution of (2-phenoxyethyl)-urea (79 mg, 0.44 mmol, from step (i)above) in dry THF (2 mL) was added dropwise n-BuLi. The mixture wasstirred at room temperature for 15 min and then the3,4-dichlorophenylisothiocyanate (89 mg, 044 mmol) in dry THF (2 mL) wasadded dropwise HPLC after 1.5 h revealed almost complete disappearanceof the starting material. Sat. NaHCO₃ (5 mL) and EtOAc (20 mL) wereadded and the phases were separated. The aq phase was extracted withanother 20 mL of EtOAc. The combined org phases were washed with water(5 mL), brine (5 mL) and were dried over MgSO₄. Conc in vacuo gave 158mg of a yellow oil HPLC-MS revealed two products with the expectedmolecular weight, m/z=384

Purification by flash chromatography (silica, 30% EtOAc in n-hexane)gave to products a: 29 mg Tr=2.875 min (ACE, 10-97% CH3CN in 3 min, 1mL/min): 73% purity, m/z=384 b: 34 mg (Fr 11-16) Tr=2.908 min (ACE,10-97% CH3CN in 3 min, 1 mL/min): 97% purity, m/z=384

The two products were not further characterized. They were cyclized intwo separate experiments.

iii) (a)5-(3,4-dichlorophenyl)imino-4-(2-phenoxyethyl)-1,2,4-thiadiazolidin-3-one;(b)5-(3,4-dichlorophenylamino)-2-(2-phenoxyethyl)-[1,2,4]thiadiazol-3-one

Cyclisation of the compounds of step (ii)(a) and (ii)(b) to the productswas performed according to the process set out in Example 1 step (ii).Purification with RP-HPLC gave the desired compounds.

5(a): MS: [M+H]: 385.0, HPLC purity: 97%, ¹H NMR (500 MHz, DMSO-d6) δppm 7.42 (d, J=8.67 Hz, 1H) 7.24-7.31 (m, 2H) 7.05 (d, J=2.44 Hz, 1H)6.99-7.03 (m, 2H) 6.92 (tt, J=7.32, 1.04 Hz, 1H) 6.87 (dd, J=8.67, 2.52Hz, 1H) 4.10-4.16 (m, 2H) 3.95-4.02 (m, 2H)

5(b)b: MS: [M+H] 385.0, HPLC purity: 100%; 1H NMR (500 MHz, DMSO-d6) δppm 11.01 (s, 1H) 8.05 (d, J=2.20 Hz, 1H) 7.62 (d, J=8.79 Hz, 1H) 7.44(dd, J=8.79, 2.44 Hz, 1H) 7.27-7.34 (m, 2H) 6.93-6.99 (m, 3H) 4.17 (t,J=4.88 Hz, 2H) 4.00 (t, J=4.88 Hz, 2H).

Example 64-Benzhydryl-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one

The following compound was formed using the same methods as describedfor Examples 1 and 5 with the appropriate starting materials, except forthe last cyclisation step where EtOAc was used instead of EtOH assolvent.

MS: m/z=428 [M+H]⁺, HPLC purity: 98% (ACE), 96% (XTerra); ¹H NMR (500MHz, DMSO-d₆) δ ppm 10.95 (br. s., 1H) 8.02 (br. s., 1H) 7.61 (d, J=8.79Hz, 1H) 7.38-7.45 (m, 5H) 7.33-7.38 (m, 2H) 7.22 (d, J=7.32 Hz, 4H) 6.62(s, 1H).

Example 7 a)4-chloro-N-[4-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benzamide

(i) N-(carbamoylcarbamothioyl)-4-chloro-benzamide

4-Chlorobenzoyl isothiocyanate (395 mg) and 600 mg urea (5 equiv) weremixed in 30 mL of acetone and stirred at reflux for 1 day. The reactionwas concentrated and the residue slurried in diethyl ether. The residuewas collected by filtration and washed with diethyl ether. The whitesolid was dissolved in ethyl acetate (10 ml) and the resultant solutionwashed with water (10 ml) and brine (10 ml), dried over MgSO₄, filteredand concentrated to a white solid (0.35 g, 1.4 mmol, 70% yield.

(ii) 4-chloro-N-(3-oxo-1,2,4-thiadiazol-5-yl)benzamide

N—(Carbamoylcarbamothioyl)-4-chloro-benzamide (350 mg) from step (i)above was mixed with 50 mL of ethyl acetate. Bromine (224 mg) in 5 mL ofethyl acetate was added. After 30 minutes 10 mL of water and 10 mL ofmethanol was added. The mixture was concentrated and the residue wastriturated with water/methanol and dried in vacuum to give the productas a white solid, 0.25 g, 0.98 mmol, 70% yield.

(iii)3,4-dichloro-N-[4-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benzamide

4-Chloro-N-(3-oxo-1,2,4-thiadiazol-5-yl)benzamide (50 mg, 0.20 mmol, 1eq) and 55 mg (0.40 mmol, 2 eq) of potassium carbonate were mixed in 5mL of DMF. 4-Fluorobenzyl bromide 38 mg (0.20 mmol, 1 eq) in 2 mL of DMFwas added dropwise. The mixture was stirred for 15 min and then thereaction mixture was diluted with 100 mL of ethyl acetate and 100 mL ofwater. The organic phase was washed with 2×100 mL of water and 50 mL ofbrine, dried over MgSO₄, filtered and concentreated. The residue waspurified with flash chromatography (silica, 40% EtOAc in hexane) to givethe product as a white solid, 8 mg, 22 umol, 11%.

1H NMR (500 MHz, DMSO-d₆) δ ppm 5.17 (s, 2H) 7.16-7.22 (m, 2H) 7.50-7.56(m, 2H) 7.61-7.65 (m, 2H) 8.19-8.23 (m, 2H) 10.46 (br. s., 1H), MS:[M+H]⁺, HPLC purity: 93%

The following compounds may be prepared according to the methodsdisclosed in for Example 7(a)

b)4-chloro-N-[4-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benzamide

c)4-chloro-N-[3-oxo-4-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazolidin-5-ylidene]benzamide

d)N-[4-[(3-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-4-(trifluoromethyl)benzamide

e)N-[4-[(3-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-3,5-bis(trifluoromethyl)benzamide

f)N-[4-[(3,4-dichlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-3,4-difluoro-benzamide

and

g)3,4-dichloro-N-[4-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benz-amide

Example 8

The following compounds, were (a to d, f, k, l, o to r and w), or may beprepared using the procedures described in Example 1 with the exceptionsthat in step (i):

-   (i) no base is used in the first step to ensure coupling of the    isothiocyanate derivative to the primary nitrogen of the urea    derivative;-   (ii) 20% DMF in acetonitrile is used as the solvent; and-   (iii) the reaction mixture was stirred for 48 h at 80° C.

a)1,5-(3,4-Dichlorophenylamino)-2-(4-methoxybenzyl)-[1,2,4]thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 3.74 (s, 3H) 4.72 (s, 2H) 6.92 (q,J=5.13 Hz, 2H) 7.24 (q, J=5.13 Hz, 2H) 7.45 (dd, J=8.79, 2.44 Hz, 1H)7.62 (d, J=8.79 Hz, 1H) 8.04 (d, J=2.44 Hz, 1H), ESI MS m/z=382 HPLCpurity: 100%;

b)1,5-(3,4-dichlorophenylamino)-2-(4-chlorobenzyl)-[1,2,4]thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.81 (s, 2H) 7.32 (d, J=8.55 Hz, 2H)7.42-7.47 (m, 3H) 7.63 (d, J=8.79 Hz, 1H) 8.05 (d, J=2.44 Hz, 1H), MS:ESI MS m/z=386 [M+H]⁺; HPLC purity: 95%;

c)1,5-(3,4-dichlorophenylamino)-2-(3,4-difluorobenzyl)-[1,2,4]thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.80 (s, 3H) 7.14-7.17 (m, 1H) 7.36-7.47(m, 3 H) 7.63 (d, J=8.79 Hz, 1H) 8.05 (d, J=2.44 Hz, 1H), ESI MS m/z=388[M+H]⁺; HPLC purity: 100%;

d)1,5-(3,4-dichlorophenylamino)-2-(3-fluorobenzyl)-[1,2,4]thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.83 (s, 2H) 7.09-7.18 (m, 3H) 7.38-7.48(m, 2 H) 7.63 (d, J=8.79 Hz, 1H) 8.05 (d, J=1.22 Hz, 1H), MS: 371[M+H]⁺, HPLC purity: 97%;

e) 1,5-(3,4-dichlorophenylamino)-2-(benzyl)-[1,2,4]thiadiazol-3-one

f) 5-(3,4-dichlorophenylamino)-2-phenethyl-[1,2,4]thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 2.89 (t, J=7.08 Hz, 2H) 3.87 (t, J=7.08Hz, 2H) 7.19-7.34 (m, 5H) 7.42 (dd, J=8.79, 2.44 Hz, 1H) 7.62 (d, J=8.79Hz, 1H) 8.02 (d, J=1.71 Hz, 1H), MS: 367 [M+H]⁺, HPLC purity: 97%;

g)2-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-5-[(3,4-dichlorophenyl)amino]-1,2,4-thiadiazol-3-one

h)2-[2-(4-chlorophenyl)sulfanylethyl]-5-[(3,4-dichlorophenyl)amino]-1,2,4-thiadiazol-3-one

i)3-[[5-[(4-chlorophenyl)amino]-3-oxo-1,2,4-thiadiazol-2-yl]methyl]-N-methyl-benzamide

j)5-[(6-chloro-3-pyridyl)amino]-2-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazol-3-one

k)2-[(3,4-difluorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.82 (s, 2H) 7.13-7.21 (m, 1H) 7.36-7.48(m, 2H) 7.72-7.77 (m, 2H) 7.78-7.84 (m, 2H), MS: 388 [M+H]⁺, HPLCpurity: 95%;

l)2-[(3,4-difluorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.79 (s, 2H) 7.12-7.20 (m, 1H) 7.33-7.49(m, 4 H) 7.70 (d, J=9.03 Hz, 2H), MS: 404 [M+H]⁺, HPLC purity: 100%;

m)5-[(4-chlorophenyl)amino]-2-[1-(4-chlorophenyl)cyclopropyl]-1,2,4-thiadiazol-3-one

n)5-[(3,4-dichlorophenyl)methylamino]-2-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazol-3-one

o)2-[(4-methoxyphenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 3.74 (s, 3H) 4.74 (s, 2H) 6.89-6.97 (m,2H) 7.22-7.29 (m, 2H) 7.71-7.76 (m, 2H) 7.76-7.82 (m, 2H), MS: 382[M+H]⁺, HPLC purity: 100%;

p)2-[(4-chlorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.82 (s, 2H) 7.29-7.36 (m, 2H) 7.41-7.47(m, 2 H) 7.73-7.77 (m, 2H) 7.77-7.83 (m, 2H), MS: 387 [M+H]⁺, HPLCpurity: 100%;

q)2-[(3-fluorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.84 (s, 2H) 7.10-7.20 (m, 3H) 7.37-7.46(m, 1H) 7.72-7.78 (m, 2H) 7.77-7.84 (m, 2H), MS: 370 [M+H]⁺, HPLCpurity: 100%;

r)2-[phenylethyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one

1H NMR (500 MHz, DMSO-d₆) δ ppm 2.90 (t, J=7.08 Hz, 2H) 3.88 (t, J=7.08Hz, 2H) 7.19-7.34 (m, 5H) 7.71-7.76 (m, 2H) 7.76-7.82 (m, 2H), MS: 360[M+H]⁺, HPLC purity: 95%;

s)2-[(4-methoxyphenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one

t)2-[(4-chlorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one

u)2-[(3-fluorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one

v)2-[phenylethyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one

and

w)4-[[2-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]amino]benzonitrile

1H NMR (500 MHz, DMSO-d₆) δ ppm 4.82 (s, 2H) 7.13-7.20 (m, 1H) 7.36-7.48(m, 2 H) 7.75-7.82 (m, 2H) 7.82-7.88 (m, 2H), MS: 345 [M+H]⁺, HPLCpurity: 95%.

Biological Tests

Descriptions of the cancer cell lines including source, tumor type, andmorphology may be obtained from the American Type Culture Collection(ATCC) or its website (www.atcc.orq). The cell lines are both fromprimary tumors and metastatic sites (for example, MCF-7, MDA-MB231,HT-29, SKOV-3 and PC-3 among others tested).

Test A Cell Proliferation Assay Reagents

Dulbecco's modified Eagle's medium (D-MEM)+1000 mg/L Glucose+GlutaMAX™1+

Pyruvate (Gibco #21885-025) V/V Foetal Bovine Serum (Gibco 10500-064)

5-bromo-2-deoxyuridine (BrdU)30 Dimethyl sulfoxide (DMSO)

PC-3 cancer cell lines were propagated in D-MEM (Gibco 21885)supplemented with 10% Foetal calf serum. 15000 cells per well wereseeded in 96 well plates and incubated overnight. The culture media waschanged to serum-free D-MEM for 24 h. The culture media was then changedto serum free D-MEM containing either 0.2% DMSO as vehicle control or0.3, 0.6, 1.2 or 2.5 μM (or 1.25, 2.5, 5, 10 μM (as indicated in Table 1below)) of the selected compounds of Example 1 to Example 8 in 0.2% DMSOin quadruplicate. After 18 h incubation, BrdU was added according tomanufacturer's recommendations. After 6 h incubation in the presence ofBrdU, the culture media was removed and BrdU incorporation was measuredusing “Cell Proliferation ELISA, BrdU colorimetric” Roche (11647229001)according to manufacturer's recommendations.

Results

Proliferation rate of PC-3 cells are reduced by relevant concentrationsof the test compounds as measured by BrdU incorporation. For example, inthe above assay, the selected compounds of Example 1 to Example 8,relative to the vehicle control (which display a BrdU incorporation of 1unit) displayed the following (approximate) units of BrdU incorporationsat the indicated concentrations in Table 1 below.

TABLE 1 Examples Units of BrdU (No) incorporation Conc (μM) 1 0.39 0.62c 0.34 0.6 2e 0.17 5 2g 0.14 10 3 0.70 10 4a 0.309 10 4b 0.72 10 4c0.393 10 4d 0.612 10 4e 0.355 10 4i 0.10 5 4l 0.20 10 4m 0.23 10 4n 0.172.5 4o 0.28 10 4p 0.26 10 5a 0.37 10 5b 0.14 10 6 0.42 1.25 8a 0.04 2.58b 0.18 2.5 8c 0.07 1.25 8f 0.08 5 8k 0.04 5 8l 0.10 5 8p 0.07 5 8q 0.155 8r 0.58 5 8w 0.28 5

Test B In Vivo Mouse Model—Test 1

5 week old Athymic BALB/cA nude mice are delivered from Taconic(Denmark) and kept under barrier conditions for 1 week acclimatisation.At 6 weeks, 17 mice are injected subcutaneously on the flank with1.8×10⁶ MDA-MB-231 human breast cancer cells (LGC Promochem-ATCC) in a50/50 v/v solution of phosphate buffered saline (PBS) (Gibco 10010-015,Invitrogen) Matrigel HC (BD Biosciences).

After 11 days, palpable tumors are observed in 16 mice. 2 mice aresacrificed and the tumors dissected and examined. 2 groups of 7 miceeach are treated once daily by intraperitoneal injections of 1-10 mg/kgbodyweight of test compound in 79% PBS/20% Solutol HS 15(BASF)/1% DMSOor vehicle control respectively for 5-30 days. The mice are sacrificedby cervical dislocation and tumors are dissected.

Histology

The tumor tissue is fixated overnight in PBS (containing 4% w/vparaformaldehyde (Scharlau PA0095, Sharlau Chemie SA, Spain) at +4° C.The tumor tissue is cryopreserved by 24 hour incubation in PBScontaining 30% w/v sucrose (BDH #1027450 (www.vwr.com) at +4° C. and isembedded in Tissue-Tek embedding media (Sakura Finetek Europa BV,Netherlands). 10 pm cryosections are generated and stained with MayersHematoxylin (Dako) for 5 minutes and destained for 3×10 minutes in tapwater. Slides are mounted using Dako faramount aqueous mounting mediumand are examined using a Nikon Eclipse TS 100 microscope documentedusing a Nikon coolpix 4500.

The tumors from mice treated with test compound and vehicle are analyzedfor morphology by microscopic examination of hematoxylin stainedcryosections.

In Vivo Mouse Model—Test 2

The above test procedure is followed, but 16 (rather than 17) mice areinjected subcutaneously.

After 6 days, palpable tumors my be observed in the 16 mice. 2 groups of8 mice each are treated once daily by intraperitoneal injections of 7.5mg/kg bodyweight of test compound in 79% PBS/20% Solutol HS 15(BASF)/1%DMSO or vehicle control respectively for 27 days. Tumor size is measuredby calliper every third day.

The results of the tumor area in the first group of mice (treated withtest compound) are compared against the second (‘untreated’) group ofmice after a certain number of days.

As will be appreciated, Test B as described above provides one of manypotential in vivo xenograft models. Modifications to Test B above may bemade (e.g. by changing some or all of: the formulation of the testcompounds; the cell line; and the type of mice used).

Test C Activation of AMPK and S-79 ACC Test Compound

Selected compounds of Examples 1, 4 to 6 and 8 were prepared. A stocksolution of 10 μM was prepared by dissolving the compound in 100% DMSO.

Cell Line and Cell Culture

Human PC3 cells were purchased from LGC Promochem-ATCC (ATCC catalog noCRL-1435). PC3 cells were maintained in Dulbecco's modified Eagle'smedium (Gibco 21885) containing 5% fetal bovine serum (Gibco 10500-064),25 μg/ml Gentamicin (Gibco 20 15750) and 1× non essential amino acids(Gibco 11140). The cells were incubated in a humidified atmosphere of 5%CO2 at 37° C. and passaged every 3 days by trypsinization. Forexperiments, PC3 cells were cultured in complete medium with 10% fetalbovine serum in 60-mm-diameter dishes, grown to 70-80% confluence andcultured in serumfree Dulbecco's modified Eagle's medium for 5 h. Cellswere then treated with 10 μM of the compound of Example 1 for 24 h. Thefinal concentration of DMSO did not exceed 0.1%, which did not affectAMPK or eEF2 phosphorylation (0.1% DMSO was used as control).

Western Blot Analysis

PC3 cells were lysed in buffer (100 mM TRIS pH 6.8, 2% w/v Sodiumdodecylsulfate (SOS), 10 mM NaF, 10 mM β-glycerophosphate, 1 mM NaVanadate). Cell debris is removed by centrifugation at 14,000×g for 15min at 4° C. and the resulting supernatant is used for Western blotting.Protein concentrations of the lysates were measured using a BCA proteinassay kit (Pierce #23225). For Western blotting, 15 μg protein wasloaded in each well of a 4-12% bis/tris gel for AMPK or S-79 ACCdetection (Criterion precast gel Bio-Rad #345-0117) and run according tomanufacturers recommendation. Gels were blotted onto a nitrocellulosefilters (Hybond-C extra Amersham #RPN203E). Filters were blocked in 20mM TRIS pH 7.5, 137 mM NaCl, 25% v/v Tween20 and 5% w/v fat freepowdered milk for 30 min. Filters were incubated overnight in blockingsolution with phospho-AMPK (Thr172) or phospho-acetyl CoA carboxylase(Cell signalling #2531 and #3661) or with a pan-AMPK antibody (Cellsignalling #2532).

Filters were washed in 20 mM TRIS pH 7.5, 137 mM NaCl, 25% v/v Tween20for 3×5 min. Filters were incubated in blocking solution with secondaryantibody, peroxidase conjugated Goat anti-rabbit IgG (JacksonimmunoResearch #111-035-003) at room temperature for 1 h. Filters werewashed as above for 3×10 min. Signal was developed with SuperSignal WestDura ECL kit (Pierce #1859024) and exposed to Hyperfilm ECL Amersham#28906837).

Results

The Western blot result showed that the compounds of selected compoundsfrom Examples 1, 4 to 6 and 8 stimulated the phosphorylation of Thr-172of the AMPK E-subunit (in comparison to control) and increasedproduction of phosphorylated acetyl co-enzyme A (a substrate of AMPK),as depicted by FIGS. 1 and 2.

Test D

In Vitro Cytotoxicity Data with Several Cell Lines in a 96 Well Plate

SRB Cytotoxicity Study

Cells are seeded and grown in the presence of varying concentrations oftest compound(s) for a period of 3 days (72 hours). The cells are thenfixed to the plate and exposed to the dye sulphorhodamine B (SRB). Thevarying amounts of inhibition of proliferation produces a standard curvefrom which the IC₅₀ value is determined.

Section A: Seeding the Cells into the Plate

96 well plates in this assay are seeded at seeding density determinedfor each cell line accordingly.

Adherent Cells:

1. Harvest cells and count. All procedures associated with harvestingand preparing cell suspensions will be carried out in a Class II hood.2. Assay uses a sterile 96 well plate cell culture plate (Microtest flatbottom tissue culture plate, Falcon 3072).3. Dilute cells to appropriate seeding density.4. Add 100 μL of the cell suspension to wells B1 to G12.5. Add 100 μL of media to all Blank wells (A1 to A12, H1 to H12).6. Incubate plate(s) overnight at 37° C. in a 5% CO₂ incubator.

Suspension Cells:

1. Harvest cells and count. All procedures associated with harvestingand preparing cell suspensions will be carried out in a Class II hood.2. Assay uses a sterile 96 well plate cell culture plate (Microtest flatbottom tissue culture plate, Falcon 3072).3. Dilute cells to appropriate seeding density.4. Add 100 μL of the cell suspension to wells B1 to G12.5. Add 100 μL of media to all Blank wells (A1 to A12, H1-H12).6. Add drugs to cells immediately after plating.

Section B: Adding Test Compound(s) to Cells

7. Prepare compound plate for test compound(s) and transfer dilutedcompound to prepared assay plate in section A.8. On compound plate add 100 μL of cell culture medium to well B3-G3 toB10-G10.9. Dilute the test articles to 250 μM in the cell culture medium in aseparate tube, which will make start concentration of 50 μM. Stockconcentration of test compound(s) is 10 mM, therefore dilute 1:40 toobtain 250 μM concentration.10. Add 200 μL of the diluted batch of drug to empty wells B2 to G2 andmix by pipetting up and down 3 times.11. Transfer 100 μL from each of these wells (using a multichannelpipette) to wells B2-G2 etc and continue to dilute 1:2 across the plateto column 10. Discard the excess 100 μL from each row in column 10.Column 11 contains DMSO control. Row 12 contains 100 μL blank medium.12. DMSO control same as drug: dilute 100% DMSO 1:40 in medium. Pipette100 μL to empty row 11 on compound plate. From this 25 μL will be addedto assay plate containing cells, which will give end concentration of0.5%.Blank control: Pipette 100 μL blank medium to row 1 and 12, 25 μL formthis will be added to assay plate containing cells.13. Using a new set of tips, transfer the drug dilutions from thecompound plate onto the assay plate containing the cells (25 μL ofdiluted drug transferred to the 100 μL of cells in the assay plate. Theend volume will be 125 μL). Start with lowest drug concentrations.14. Incubate the assay plate at 37° C. in a 5% CO₂ incubator for 3 days.

Section C: Fixing and Staining the Cells

At the end of the incubation period the cells will need to be fixed andthe SRB assay performed as described below:

1. Transfer the plate from the incubator in the cell culture suite to 4°C., leave cells for an hour.2. Adherent cell lines: Fix cells to the plate by carefully adding 30 μLof cold 50% v/v Trichloroacetic acid (TCA BDH 102863H) to the cellculture medium already in the wells so the final concentration of TCA is10% v/v.

Suspension cell lines: Fix cells to the plate by carefully adding 30 μLof cold 80% v/v Trichloroacetic acid (TCA BDH 102863H) to the cellculture medium already in the wells so the final concentration of TCA is16% v/v.

1. Incubate at 4° C. for 1 hour.2. Submerge plate in a plastic container containing distilled water suchthat each well fills with water. Leave to soak for 1 minute. Flick offwash solution into the sink and repeat this washing step a further fourtimes. Finally, flick off wash solution and leave to air dry.3. When wells are completely dry add 100 μl of 0.4% w/v Sulforhodamine B(SRB Sigma S1402) in 1% v/v acetic acid to each well and incubate atroom temperature for 30 minutes.4. Flick off SRB and wash four times by submerging the plates for 1minute in 1% v/v acetic acid. Flick off wash solution and leave to airdry.5. When wells are completely dry add 100 μl of 10 mM Tris base pH 10.5(pH adjusted to 10.5 using sodium hydroxide solution). Place on a plateshaker and mix for 5 min. Read the plate at 564 nm using the SPECTRAmaxmicroplate spectrophotometer acquiring data.

Test E Clonogenic Assay Results Section A: Seeding the Assay Plates

24 well plates (Falcon Cat no: 353047) in this assay are seeded atseeding density determined for each cell line accordingly.

Base Agar:

-   -   1. Melt 1.6% Agar (invitrogen Select Agar) in microwave, and        cool to 40-42° C. in a waterbath.    -   2. Warm cell culture Media+20% FBS+2× of any other cell culture        supplements required to 40-42° C. in waterbath. Allow at least        30 minutes for temperature to equilibrate.    -   3. Mix equal volumes of the two solutions to give 0.8%        Agar+Media+10% FBS+1× cell culture supplements.    -   4. Add 0.2 ml/well, allow setting. The plates can be stored at        4° C. for up to 1 week.

Top Agar:

-   -   1. Melt 0.8% Agar (invitrogen Select Agar) in microwave, and        cool to 40° C. in a waterbath.    -   2. Warm Media+20% FBS+2× of any other cell culture supplements        required to the same temperature.    -   3. Harvest cells and count. All procedures associated with        harvesting and preparing cell suspensions will be carried out in        a Class II hood.    -   4. Dilute cells in Media to appropriate seeding density.    -   5. Label the 24 well plates with base agar appropriately (if the        plate is stored in the refrigerator, remove the plate from 4° C.        about 30 minutes prior to plating to allow them to warm up to        room temperature).    -   6. For plating mix equal volumes of Media+20% FBS+2× cell        culture supplements+ cells and soft Agar 0.8% solution to a 15        ml capped centrifuge tube, mix gently and add 0.2 ml to each        replicate well (usually plate out in quadruplicate).    -   7. Incubate plate(s) overnight at 37° C. in a 5% CO₂ incubator

Section B: Adding Test Compound to Cells

-   -   1. Prepare compound plate for test compound(s) and then transfer        diluted compound to prepared assay plate in section A.    -   2. Dilute the test compound(s) to 120 μM in the cell culture        medium in a separate tube, which will make start concentration        of 40 μM.    -   Stock concentration of test compound(s) is 10 mM, therefore        dilute 1:83.3 to obtain 120 WI concentration.    -   3. Make dilutions of the drug test solution by 1:2, 3 times from        the start concentration of 120 μM to prepare the test drug        concentrations at 20, 10 and 5 μM.    -   4. Transfer 2004 from each test concentration to each well by        quadruplicate. Column 6 contains 40 μM test compound(s). Column        5 contains 20 μM test compound(s), Column 4 contains 10 μM test        compound(s), and Column 3 contains 5 μM test compound(s).    -   5. DMSO controls same as drug: dilute 100% DMSO 1:83.3 in        medium. Pipette 200 μL to Column 2 on compound plate by        quadruplicate., which will give end concentration of 0.4%.    -   6. Blank control: Pipette 200 μL blank medium per well to Column        1 by quadruplicate.    -   7. Incubate the assay plate at 37° C. in a 5% CO₂ incubator for        2-3 weeks.

Section C: Staining and Counting the Cell Colonies

At the end of the incubation period the cell colonies will need to bestained and count as described below:

-   -   1. Mark the bottom of each well dividing each well at least in        four sections.    -   2. Stain plates with 0.2 ml of 0.005% Crystal Violet for 1 hour        at 37° C. 5% CO₂ in a humidified incubator.    -   3. Count the colonies per well for each test group using a        dissecting microscope.    -   4. To consider a group of cells as a colony at least each colony        must have 50 cells.    -   5. Calculate the average of number of colonies of each well per        group and calculate the % of inhibition of cell colonies        formation produced by test compound using the formula % T/C, in        which T is the test group and C is the controls.

Test F Dephosphorylation of PP2C Assay

Hyperphosphosphorylated AMPK trimer 10 (ng) (α1/β1/γ1) from Invitrogen(PV4672) was incubated in a buffer containing: 40 mM Hepes pH 7.45, 2 mMMnCl₂, 0.5 mM DTT and 0.125 ng recombinant PP2C-α1 (Abcam Ab51205) inthe presence or absence of potential inhibitors of theinteraction/enzymatic reaction in at total volume of 10 μL for 20minutes in 30° C. The reaction was terminated by addition of 40 μL stopsolution containing 1% Bovine Serum Albumin (BSA), 10 mM EDTA and antiPhospho-AMPKα (Thr172) Antibody(cell signaling #2531) at a dilution of1/1000. The samples were transferred to glutathione coated 96 wellplated (Pierce #15140) and incubated 0/N at +4° C. The plate was washed3×200 μL in PBS/0.05% Triton X-100. The plate was incubated with PBS/1%BSA and horse radish peroxidase conjugated goat-anti rabbit antibody(Jackson immunoresearch Laboratories Inc. #111-035-003) at a dilution of1/10 000 for 2 h in room temperature. The plate was washed 3×200 μL inPBS/0.05% Triton X-100. The assay was developed by addition of 100 μLLiquid Substrate System for ELISA(Sigma, T0440) for 5-30 min. Thedeveloping reaction was terminated by addition of 25 μL 1M in each well.Absorbance was measured at 450 nm, where absorbance correlates to amountp-T172 AMPK.

Results

As illustrated in FIG. 3, the compounds of Example 1 and Example 2c havethe ability to reduce PP2C-al mediated dephosphorylation of AMPK.

1-34. (canceled)
 35. A compound of formula I,

wherein: A represents C(═N—W-D) or S; B represents S or C(—NH—W-D);when: A represents C(═N—W-D) and B represents S then the bond between Band the NH atom is a single bond; or A represents S and B representsC(—NH—W-D) then the bond between B and the NH atom is a double bond; Xrepresents -Q-[CR^(x)R^(y)]_(n)—; W represents —[CR^(x)R^(y)]_(m)— or—C(O)—[CR^(x)R^(y)]_(p)—; Q represents a bond, —N(R⁸)—, —S—, or —O—; A₁to A₅ respectively represent C(R¹), C(R²), C(R³), C(R⁴) and C(R⁵), or,alternatively, up to two of A₁ to A₅ may independently represent N; Drepresents phenyl, pyridyl or pyrimidinyl optionally substituted by oneor more R⁶ groups; R^(x) and R^(y), on each occasion when used herein,are independently selected from H, halo, C₁₋₆ alkyl (optionallysubstituted by one or more halo atoms), aryl (optionally substituted byone or more halo atoms) or R^(x) and R^(y) are linked to form, alongwith the carbon atom to which they are attached, a non-aromatic 3- to8-membered ring, optionally containing 1 to 3 heteroatoms selected fromO, S and N, which ring is itself optionally substituted by one or moresubstituents selected from halo or C₁₋₆ alkyl (optionally substituted byone or more halo atoms); R¹ to R⁵ independently represent H, halo, —R⁷,—CF₃, —CN, —NO₂, —C(O)R⁷, —C(O)OR⁷, —C(O)—N(R^(7a))R^(7b),—N(R^(7a))R^(7b), —N(R⁷)₃ ⁺, —SR⁷, —OR⁷, —NH(O)R⁷, —SO₃R⁷, aryl orheteroaryl (which aryl and heteroaryl groups are themselves optionallyand independently substituted by one or more groups selected from haloand R¹⁶), or any two of R¹ to R⁵ which are adjacent to each other areoptionally linked to form, along with two atoms of the essential benzenering in the compound of formula I, an aromatic or non-aromatic 3- to8-membered ring, optionally containing 1 to 3 heteroatoms selected fromO, S and N, which ring is itself optionally substituted by one or moresubstituents selected from halo, —R⁷, —OR⁷ and ═O; R⁶ independentlyrepresents, on each occasion when used herein, cyano, —NO₂, halo, —R⁸,—OR⁸, —N(R⁸)C(O)R⁸, —NR⁹R¹⁰, —SR¹¹, —Si(R¹²)₃, —OC(O)R¹³, —C(O)OR¹³,—C(O)R¹⁴, —C(O)NR^(15a)R^(15b), —S(O)₂NR^(15c)R^(15d), aryl orheteroaryl (which aryl and heteroaryl groups are themselves optionallyand independently substituted by one or more groups selected from haloand R¹⁶), or any two R⁶ groups which are adjacent to each other areoptionally linked to form, along with two atoms of the essential benzenering in the compound of formula I, an aromatic or non-aromatic 3- to8-membered ring, optionally containing 1 to 3 heteroatoms selected fromO, S and N, which ring is itself optionally substituted by one or moresubstituents selected from halo, —R⁷, —OR⁷ and ═O; R⁷, on each occasionwhen used herein, is selected from H or C₁-C₆ alkyl, C₁-C₆ cycloalkyl,aryl and heteroaryl (wherein the latter four groups are optionallysubstituted by one or more halo atoms); R^(7a) and R^(7b) areindependently selected from H, or C₁-C₆ alkyl, C₁-C₆ cycloalkyl, aryland heteroaryl, or R^(7a) and R^(7b) are optionally linked to form,along with the nitrogen atom to which they are attached, an aromatic ornon-aromatic 3- to 8-membered ring, optionally containing 1 to 3heteroatoms selected from O, S and N, which ring is itself optionallysubstituted by one or more substituents selected from halo, —R⁷, —OR⁷and ═O; R^(a), R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(15a), R^(15b),R^(15c) and R^(15d), on each occasion where used herein, independentlyrepresent H or R¹⁶; R¹⁶ represents, on each occasion when used herein,C₁₋₆ alkyl optionally substituted by one or more halo atoms; nrepresents 1 or 2; m represents 0, 1 or 2; p represents 0, 1 or 2; or apharmaceutically-acceptable salt or solvate, or a pharmaceuticallyfunctional derivative thereof, provided that: (A) when D is phenyl, thenat least one of A₁ to A₅ is not (C—H) and/or D is substituted by one ormore —R⁶ groups, and: further provided that: (B) when X represents—CH₂—, the A₁ to A₅-containing ring represents unsubstituted phenyl, Arepresents S, B represents C(—NH—W-D), W represents —[CR^(x)R^(y)]_(m)—in which m represents 0, then D does not represent 2,4-6-tri-nitrophenyl.
 36. A compound as claimed in claim 35, wherein eachR⁶ independently represents —CN, —CF₃, —OCF₃, —F or —Cl.
 37. A compoundas claimed in claim 35, wherein at least one of A₁ to A₅ is not (C—H)and/or D is substituted by one or more —R⁶ groups.
 38. A compound offormula I as claimed in claim 35, wherein B represents S.
 39. A compoundof formula I as claimed in claim 35, wherein R^(x) and R^(y) areindependently selected from H, C₁₋₆ alkyl (optionally substituted by oneor more fluoro atoms), aryl (optionally substituted by one or more halo,e.g. chloro atoms) or R^(x) and R^(y) are linked to form, along with thecarbon atom to which they are attached, a non-aromatic 3- to 6-memberedunsubstituted ring.
 40. A compound of formula I as claimed in claim 35,wherein X represents —CH₂—, —CH₂CH₂—, —O—CH₂CH₂—, —N(CH₃)—CH₂CH₂—,—S—CH₂CH₂—, 1,1-cyclopropyl or —C(H)(4-chlorophenyl)-.
 41. A compound offormula I as claimed in claim 35, wherein at least one of R¹ to R⁵, whenpresent, represents halo, —R⁷, —CF₃, —CN, —C(O)R⁷, —C(O)OR⁷,—C(O)—N(R^(7a))R^(7b), —N(R⁷)₃ ⁺, —SR⁷, —OR⁷ or —NH(O)R⁷, or any two ofR¹ to R⁵ which are adjacent to each other are optionally linked to form,along with two atoms of the essential benzene ring in the compound offormula I, an aromatic or non-aromatic 3- to 8-membered ring, optionallycontaining 1 to 3 heteroatoms selected from O, S and N, which ring isitself optionally substituted by one or more substituents selected fromhalo, —R⁷, —OR⁷ and ═O.
 42. A compound of formula I as claimed in claim41, wherein at least one of R¹ to R⁵, when present, represents4H-[1,2,4]-triazolyl, —OR⁷, —Cl, —F, —CF₃, —CN or —C(O)—N(R^(7a))R^(7b).43. A compound of formula I as claimed in claim 35, wherein R⁶independently represents —C(O)NR^(15a)R^(15b), cyano, —NO₂, —Br, —Cl,—F, —R⁸, —OR⁸, —NR⁹R¹⁰, —C(O)OR¹³, —C(O)R¹⁴, —S(O)₂NR^(15c)R^(15d), arylor heteroaryl (which aryl and heteroaryl groups are themselvesoptionally and independently substituted by one or more groups selectedfrom halo and R¹⁶), or any two R⁶ groups which are adjacent to eachother are optionally linked to form, along with two atoms of theessential benzene ring in the compound of formula I, quinoline,tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline, wherein theadditional ring system of the quinoline, tetrahydroquinoline,isoquinoline or tetrahydroisoquinoline moiety is itself optionallysubstituted by one or more substituents selected from halo, —R⁷, —OR⁷and ═O.
 44. A compound of formula I as claimed in claim 43, wherein R⁶independently represents —R⁶, —CN, —OCF₃, —NO₂, —Br, —Cl, —F, —OR⁸,—NR⁹R¹⁰ or —SR¹¹.
 45. A compound of formula I as claimed in claim 35,wherein n represents 1 or 2; m represents 0 or 1; and/or p represents 0or
 1. 46. A compound of formula I as claimed in claim 35, wherein Wrepresents a direct bond, —CH₂—, —C(O)— or —C(O)CH₂—.
 47. A compound asclaimed in claim 45, wherein W represents —C(O)— or —C(O)CH₂—.
 48. Acompound as claimed in claim 35, which is selected from the group: i)5-(3,4-dichlorophenyl)imino-4-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazolidin-3-one;ii)5-(3,4-dichlorophenyl)imino-4-[(4-methoxyphenyl)methyl]-1,2,4-thiadiazolidin-3-one;iii)4-[(4-chlorophenyl)methyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one;iv)5-(3,4-dichlorophenyl)imino-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one;v)5-(3,4-dichlorophenyl)imino-4-[(3-fluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one;vi)5-(3,4-dichlorophenyl)imino-4-[phenyl)methyl]-1,2,4-thiadiazolidin-3-one;vii) 5-(3,4-dichlorophenyl)imino-4-phenethyl-1,2,4-thiadiazolidin-3-one;viii)4-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thia-diaz-olidin-3-one;ix)4-[2-(4-chlorophenyl)sulfanylethyl]-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one;x)3-[[(5-(3,4-dichlorophenyl)imino-3-oxo-1,2,4-thiadiazolidin-4-yl]methyl]-N-methylbenz-amide;xi)5-[(6-chloro-3-pyridyl)imino]-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one;xii)4-[[4-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]amino]benzo-nitrile;xiii)4-[(3,4-difluorophenyl)methyl]-5-[(4-(trifluoromethyl)phenyl]imino-1,2,4-thiadiazolidin-3-one;xiv)4-[(3,4-difluorophenyl)methyl]-5-[4-(trifluoromethoxy)phenyl]imino-1,2,4-thiadiazolidin-3-one;xv)3-[5-(3,4-dichlorophenyl)imino-3-oxo-1,2,4-thiadiazolidin-4-yl]methyl]benzonitrile;xvi)5-(3,4-dichlorophenyl)imino-4-[[4-(1,2,4-triazol-1-yl)phenyl]methyl]-1,2,4-thiadiaz-olidin-3-one;xvii)4-[1-(4-chlorophenyl)cyclopropyl]-5-(4-chlorophenyl)imino-1,2,4-thiadiazolidin-3-one;xviii)5-[(4-chlorophenyl)methylimino]-4-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazolidin-3-one;N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]benzamide;xix)4-fluoro-N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]benzamide;xx)2-(4-fluorophenyl)-N-[3-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazol-5-yl]acetamide;xxi)4-chloro-N-[2-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxii)4-chloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxiii)4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxiv)4-chloro-N-[2-[2-(phenoxy)ethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxv)4-chloro-N-[2-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxvi)4-chloro-N-[2-[2-(4-chlorophenyl)sulfanylethyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxvii)3,4-dichloro-N-[2-[1-(4-fluorophenyl)cyclopropyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxviii)3,4-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxix)N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-4-methoxy-benzamide;xxx)2,6-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxxi)2,4-dichloro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxxii)N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-4-(trifluoromethoxy)-benzamide;xxxiii)N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]-3,5-bis(trifluoromethyl)-benzamide;xxxiv)3,4-difluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxxv)2-chloro-6-fluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide;xxxvi)3,5-difluoro-N-[2-[(4-fluorophenyl)methyl]-3-oxo-1,2;4-thiadiazol-5-yl]benzamide;xxxvii)5-(3,4-dichlorophenyl)imino-4-(2-phenoxyethyl)-1,2,4-thiadiazolidin-3-one;xxxviii)5-(3,4-dichlorophenylamino)-2-(2-phenoxyethyl)-[1,2,4]thiadiazol-3-one;xxxix)4-benzhydryl-5-(3,4-dichlorophenyl)imino-1,2,4-thiadiazolidin-3-one; xl)4-chloro-N-[4-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benzamide;xli)4-chloro-N-[4-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benzamide;xlii)4-chloro-N-[3-oxo-4-[[3-(trifluoromethyl)phenyl]methyl]-1,2,4-thiadiazolidin-5-ylidene]-benzamide;xliii)N-[4-[(3-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-4-(trifluoromethyl)-benzamide;xliv)N-[4-[(3-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-3,5-bis(trifluoro-methyl)benzamide;xlv)N-[4-[(3,4-dichlorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]-3,4-difluoro-benzamide;xlvi)1,5-(3,4-dichlorophenylamino)-2-(4-methoxybenzyl)-[1,2,4]thiadiazol-3-one;xlvii)1,5-(3,4-dichlorophenylamino)-2-(4-chlorobenzyl)-[1,2,4]thiadiazol-3-one;xlviii)1,5-(3,4-dichlorophenylamino)-2-(3,4-difluorobenzyl)-[1,2,4]thiadiazol-3-one;xlix)1,5-(3,4-dichlorophenylamino)-2-(3-fluorobenzyl)-[1,2,4]thiadiazol-3-one;l) 1,5-(3,4-dichlorophenylamino)-2-(benzyl)-[1,2,4]thiadiazol-3-one; li)5-(3,4-dichlorophenylamino)-2-phenethyl-[1,2,4]thiadiazol-3-one; lii)2-[2-[(4-chlorophenyl)-methyl-amino]ethyl]-5-[(3,4-dichlorophenyl)amino]-1,2,4-thiadiazol-3-one;liii)2-[2-(4-chlorophenyl)sulfanylethyl]-5-[(3,4-dichlorophenyl)amino]-1,2,4-thiadiazol-3-one;liv)3-[[5-[(4-chlorophenyl)amino]-3-oxo-1,2,4-thiadiazol-2-yl]methyl]-N-methyl-benzamide;lv)5-[(6-chloro-3-pyridyl)amino]-2-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazol-3-one;lvi)2-[(3,4-difluorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;lvii)2-[(3,4-difluorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;lviii)5-[(4-chlorophenyl)amino]-2-[1-(4-chlorophenyl)cyclopropyl]-1,2,4-thiadiazol-3-one;lix)5-[(3,4-dichlorophenyl)methylamino]-2-[(3,4-difluorophenyl)methyl]-1,2,4-thiadiazol-3-one;lx)3,4-dichloro-N-[4-[(4-fluorophenyl)methyl]-3-oxo-1,2,4-thiadiazolidin-5-ylidene]benz-amide;lxi)2-[(4-methoxyphenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;lxii)2-[(4-chlorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;lxiii)2-[(3-fluorophenyl)methyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;lxiv)2-[phenylethyl]-5-[[4-(trifluoromethyl)phenyl]amino]-1,2,4-thiadiazol-3-one;lxv)2-[(4-methoxyphenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;lxvi)2-[(4-chlorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;lxvii)2-[(3-fluorophenyl)methyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;lxviii)2-[phenylethyl]-5-[[4-(trifluoromethoxy)phenyl]amino]-1,2,4-thiadiazol-3-one;and lxix)4-[[2-[(3,4-difluorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]amino]benzonitrile.49. A pharmaceutical formulation including a compound as defined inclaim 35, or a pharmaceutically-acceptable salt or solvate, or apharmaceutically functional derivative thereof, but without proviso (B),in admixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.
 50. A combination product comprising: (A) a compound of formulaI as defined in claim 35, or a pharmaceutically-acceptable salt orsolvate, or a pharmaceutically functional derivative thereof, butwithout proviso (B); and (B) another therapeutic agent useful in thetreatment of cancer, wherein each of components (A) and (B) isformulated in admixture with a pharmaceutically-acceptable adjuvant,diluent or carrier.
 51. A combination product as claimed in claim 50which comprises a pharmaceutical formulation including the compound offormula I, or a pharmaceutically-acceptable salt or solvate, or apharmaceutically functional derivative thereof but without proviso (B);another therapeutic agent useful in the treatment of cancer; and apharmaceutically-acceptable adjuvant, diluent or carrier.
 52. Acombination product as claimed in claim 50, which comprises a kit ofparts comprising components: (a) a pharmaceutical formulation includingthe compound of formula I, or a pharmaceutically-acceptable salt orsolvate, or a pharmaceutically functional derivative thereof, butwithout proviso (B), in admixture with a pharmaceutically-acceptableadjuvant, diluent or carrier; and (b) a pharmaceutical formulationincluding another therapeutic agent useful in the treatment of cancer inadmixture with a pharmaceutically-acceptable adjuvant, diluent orcarrier, which components (a) and (b) are each provided in a form thatis suitable for administration in conjunction with the other.
 53. A kitof parts as claimed in claim 52, wherein components (A) and (B) aresuitable for sequential, separate and/or simultaneous use in thetreatment of cancer.
 54. A combination product as claimed in claim 50,wherein the other therapeutic agent is selected from: (i) a cytostatic,or a pharmaceutically-acceptable salt, solvate or pharmaceuticallyfunctional derivative thereof; (ii) an angiogenesis inhibitor, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative thereof; (iii) tamoxifen, or a pharmaceutically-acceptablesalt, solvate or pharmaceutically functional derivative thereof; (iv) anaromatase inhibitor, or a pharmaceutically-acceptable salt, solvate orpharmaceutically functional derivative thereof; (v) trastuzumab(Herceptin), or another antibody that is useful in the treatment ofcancer; (vi) a tyrosine kinase inhibitor, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative thereof; (vii) a glitazone, or a pharmaceutically-acceptablesalt, solvate or pharmaceutically functional derivative thereof; (viii)biguanides, or a pharmaceutically-acceptable salt, solvate orpharmaceutically functional derivative thereof; (ix) a statin, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative thereof; (x) an inhibitor of activity of the mammalian targetof rapamycin (mTOR), or a pharmaceutically-acceptable salt, solvate orpharmaceutically functional derivative thereof; (xi) an oligomycin, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative thereof; (xii) AICAR (aminoimidazole carboxamideribonucleotide), or a pharmaceutically-acceptable salt, solvate orpharmaceutically functional derivative thereof; (xiii) a peroxisomeproliferator-activated receptor (PPAR) agonist, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative thereof; (xiv) A-769662, or a pharmaceutically-acceptablesalt, solvate or pharmaceutically functional derivative thereof; (xv)D942(5-(3-(4-(2-(4-Fluorophenyl)ethoxy)-phenyl)propyl)furan-2-carboxylicacid), or a pharmaceutically-acceptable salt, solvate orpharmaceutically functional derivative thereof; (xvi) AM251, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative thereof; (xvii) a SIRT1 activator, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative thereof; and/or (xviii) salidroside, or apharmaceutically-acceptable salt, solvate or pharmaceutically functionalderivative thereof.
 55. A combination product as claimed in claim 54,wherein the other therapeutic agent is selected from cisplatin,doxorubicin, tamoxifen, anastrozole, letrozole, exemastane, herceptin,imatinib, gefitinib, erlotinib, canertinib, sunitinib, zactima,vatalanib, sorafenib, leflunomide, lapatinib, rosiglitazone, metformin,fluvastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin,lovastatin and rapamycin.
 56. A combination product as claimed in claim55, wherein the other therapeutic agent is selected from cisplatin,doxorubicin, tamoxifen and herceptin.
 57. A method of inhibiting cellproliferation, which method comprises the administration of an effectiveamount of a compound of formula I as defined in claim 35, or apharmaceutically-acceptable salt or solvate, or a pharmaceuticallyfunctional derivative thereof but without proviso (B), or apharmaceutical formulation including the compound of formula I, or apharmaceutically-acceptable salt or solvate, or a pharmaceuticallyfunctional derivative thereof but without proviso (B); and anothertherapeutic agent useful in the treatment of cancer; and apharmaceutically-acceptable adjuvant, diluent or carrier, to a patientin need of such treatment.
 58. A method of treatment of cancer, whichmethod comprises the administration of an effective amount of a compoundof formula I as defined in claim 35, or a pharmaceutically-acceptablesalt or solvate, or a pharmaceutically functional derivative thereof butwithout proviso or (B), a pharmaceutical formulation including thecompound of formula I, or a pharmaceutically-acceptable salt or solvate,or a pharmaceutically functional derivative thereof but without proviso(B); and another therapeutic agent useful in the treatment of cancer;and a pharmaceutically-acceptable adjuvant, diluent or carrier, to apatient in need of such treatment, to a patient in need of suchtreatment.
 59. A method as claimed in claim 58, wherein the cancer is asolid tumor or a hematopoietic tumor.
 60. A method as claimed in claim59, where the cancer is a solid tumor of the colon, the breast or theprostate.
 61. A method as claimed in claim 59, wherein the cancer is ofthe breast.
 62. A method as claimed in claim 59, where the cancer is ahematopoietic tumor that is a leukemia.
 63. A kit of parts comprising:(I) one of components (a) and (b) as defined in claim 52, together with(II) instructions to use that component in conjunction with the other ofthe two components.
 64. A method of making a kit of parts as defined inclaim 52, which method comprises bringing a component (a) intoassociation with a component (b), thus rendering the two componentssuitable for administration in conjunction with each other.
 65. A methodof treatment of diabetes, which method comprises the administration ofan effective amount of a compound of formula I as defined in claim 35,or a pharmaceutically-acceptable salt or solvate, or a pharmaceuticallyfunctional derivative thereof but without proviso (B), to a patient inneed of such treatment.
 66. A method as claimed in claim 65, wherein thediabetes is type 2 diabetes.
 67. A process for the preparation of acompound of formula I as defined in claim 35, (i) for compounds offormula I wherein A represents S, cyclisation of a compound of formulaIIa,

wherein A₁ to A₅, X, W and D are as defined in claim 35; (ii) forcompounds of formula I wherein A represents S, W represents—[CR^(x)R_(y)]_(m)— and m represents 1 or 2, reaction of a compound offormula III,

wherein A₁ to A₅ and X are as defined in claim 35, with a compound offormula IV,L₂-W¹-D  IV wherein L₂ represents a suitable leaving group, W¹represents —[CR^(x)R^(y)]_(m)— in which m represents 1, and D is asdefined in claim 35; (iii) for compounds of formula I wherein Arepresents S, W represents —[CR^(x)R^(y)]_(m)— and m represents 0,reaction of a compound of formula III as hereinbefore defined with acompound of formula V,L₃-D  V wherein L₃ is a suitable leaving group and D is as defined inclaim 35; (iv) for compounds of formula I wherein A represents S, Wrepresents —C(O)—[CR^(x)R^(y)]_(p)—, reaction of a compound of formulaIII as hereinbefore defined, with a compound of formula VI,L₄-W²-D  VI wherein L₄ is a suitable leaving group or —OH, W² represents—C(O)—[CR^(x)R^(y)]_(p)—, and D is as defined in claim 35; (v) forcompounds of formula I wherein A represents S, and Q is a bond, —O— or—S—, reaction of a compound of formula VII,

wherein W and D are as defined in claim 35, with a compound of formulaVIII,

wherein A₁ to A₅, n, R^(x) and R^(y) are as defined in claim 35, L₅ is asuitable leaving group and Q is a bond, —O— or —S—; (vi) for compoundsof formula I wherein W is —[CR^(x)R^(y)]_(m)—, reaction of a compound offormula IX,

wherein L₆ represents a suitable leaving group and A₁ to A₅ and X are asdefined in claim 35, with a compound of formula X,H₂N—W-D  X wherein W and D are as defined in claim 35; and vii) forcompounds of formula I wherein B represents S, cyclisation of a compoundof formula IIb,

wherein A₁ to A₅, X, W and D are as defined in claim 35 above.
 68. Aprocess for the preparation of a pharmaceutical formulation as definedin claim 49, which process comprises bringing into association thecompound of formula I, or a pharmaceutically-acceptable salt or solvate,or a pharmaceutically functional derivative thereof but without proviso(B), with a pharmaceutically-acceptable adjuvant, diluent or carrier.69. A process for the preparation of a combination product as defined inclaim 50, which process comprises bringing into association the compoundof formula I, or a pharmaceutically-acceptable salt or solvate, or apharmaceutically functional derivative thereof but without proviso (B),with the other therapeutic agent that is useful in the treatment ofcancer.